AU2011219764A1 - Thienopyrimidines containing a substituted alkyl group for pharmaceutical compositions - Google Patents

Abstract

The present invention relates to novel thienopyhmidine compounds of general formula pharmaceutical compositions comprising these compounds and their therapeutic use for the prophylaxis and/or treatment of diseases which can be influenced by the inhibition of the kinase activity of Mnk1 and/or Mnk2 (Mnk2a or Mnk2b) and/or variants thereof.

Description

WO 2011/104340 PCT/EP2011/052813 Thienopyrimidines containing a substituted alkyl group for pharmaceutical compositions The present invention relates to thienopyrimidine compounds and to novel 5 pharmaceutical compositions comprising thienopyrimidine compounds. Moreover, the present invention relates to the use of the thienopyrimidine compounds of the invention for the production of pharmaceutical compositions for the prophylaxis and/or treatment of diseases which can be influenced by the inhibition of 10 the kinase activity of Mnk1 (Mnkla or MnK1b) and/or Mnk2 (Mnk2a or Mnk2b) or further variants thereof. Particularly, the present invention relates to the use of the thienopyrimidine compounds of the invention for the production of pharmaceutical compositions for the prophylaxis and/or therapy of metabolic diseases, such as diabetes, hyperlipidemia and obesity, hematopoietic disorders, neurodegenerative 15 diseases, kidney damage, inflammatory disorders, and cancer and their consecutive complications and disorders associated therewith. Metabolic diseases are diseases caused by an abnormal metabolic process and may either be congenital due to an inherited enzyme abnormality or acquired due to a 20 disease of an endocrine organ or failure of a metabolically important organ such as the liver or the pancreas. The present invention is more particularly directed to the treatment and/or prophylaxis of in particular metabolic diseases of the lipid and carbohydrate 25 metabolism and the consecutive complications and disorders associated therewith. Lipid disorders cover a group of conditions which cause abnormalities in the level and metabolism of plasma lipids and lipoproteins. Thus, hyperlipidemias are of particular clinical relevance since they constitute an important risk factor for the 30 development of atherosclerosis and subsequent vascular diseases such as coronary heart disease. Diabetes mellitus is defined as a chronic hyperglycemia associated with resulting damages to organs and dysfunctions of metabolic processes. Depending on its WO 2011/104340 PCT/EP2011/052813 etiology, one differentiates between several forms of diabetes, which are either due to an absolute (lacking or decreased insulin secretion) or to a relative lack of insulin. Diabetes mellitus Type I (IDDM, insulin-dependent diabetes mellitus) generally occurs in adolescents under 20 years of age. It is assumed to be of auto-immune 5 etiology, leading to an insulitis with the subsequent destruction of the beta cells of the islets of Langerhans which are responsible for the insulin synthesis. In addition, in latent autoimmune diabetes in adults (LADA; Diabetes Care. 8: 1460-1467, 2001) beta cells are being destroyed due to autoimmune attack. The amount of insulin produced by the remaining pancreatic islet cells is too low, resulting in elevated blood 10 glucose levels (hyperglycemia). Diabetes mellitus Type II generally occurs at an older age. It is above all associated with a resistance to insulin in the liver and the skeletal muscles, but also with a defect of the islets of Langerhans. High blood glucose levels (and also high blood lipid levels) in turn lead to an impairment of beta cell function and to an increase in beta cell apoptosis. 15 Diabetes is a very disabling disease, because today's common anti-diabetic drugs do not control blood sugar levels well enough to completely prevent the occurrence of high and low blood sugar levels. Out of range blood sugar levels are toxic and cause long-term complications for example retinopathy, renopathy, neuropathy and 20 peripheral vascular disease. There is also a host of related conditions, such as obesity, hypertension, heart disease and hyperlipidemia, for which persons with diabetes are substantially at risk. Obesity is associated with an increased risk of follow-up diseases such as 25 cardiovascular diseases, hypertension, diabetes, hyperlipidemia and an increased mortality. Diabetes (insulin resistance) and obesity are part of the "metabolic syndrome" which is defined as the linkage between several diseases (also referred to as syndrome X, insulin-resistance syndrome, or deadly quartet). These often occur in the same patients and are major risk factors for development of diabetes type 11 and 30 cardiovascular disease. It has been suggested that the control of lipid levels and glucose levels is required to treat diabetes type 11, heart disease, and other occurrences of metabolic syndrome (see e.g., Diabetes 48: 1836-1841, 1999; JAMA 288: 2209-2716, 2002). 2 WO 2011/104340 PCT/EP2011/052813 In one embodiment of the present invention the compounds and compositions of the present invention are useful for the treatment and/or prophylaxis of metabolic diseases of the carbohydrate metabolism and their consecutive complications and 5 disorders such as impaired glucose tolerance, diabetes (preferably diabetes type 11), diabetic complications such as diabetic gangrene, diabetic arthropathy, diabetic osteopenia, diabetic glomerosclerosis, diabetic nephropathy, diabetic dermopathy, diabetic neuropathy, diabetic cataract and diabetic retinopathy, diabetic maculopathy, diabetic feet syndrome, diabetic coma with or without ketoacidosis, diabetic 10 hyperosmolar coma, hypoglycemic coma, hyperglycemic coma, diabetic acidosis, diabetic ketoacidosis, intracapillary glomerulonephrosis, Kimmelstiel-Wilson syndrome, diabetic amyotrophy, diabetic autonomic neuropathy, diabetic mononeuropathy, diabetic polyneuropathy, diabetic angiopathies, diabetic peripheral angiopathy, diabetic ulcer, diabetic arthropathy, or obesity in diabetes. 15 In a further embodiment the compounds and compositions of the present invention are useful for the treatment and/or prophylaxis of metabolic diseases of the lipid metabolism (i.e. lipid disorders) and their consecutive complications and disorders such as hypercholesterolemia, familial hypercholesterolemia, Fredrickson's 20 hyperlipoproteinemia, hyperbetalipoproteinemia, hyperlipidemia, low-density lipoprotein-type [LDL] hyperlipoproteinemia, pure hyperglyceridemia, endogenous hyperglyceridemia, isolated hypercholesterolemia, isolated hypertroglyceridemia, cardiovascular diseases such as hypertension, ischemia, varicose veins, retinal vein occlusion, atherosclerosis, angina pectoris, myocardial infarction, stenocardia, 25 pulmonary hypertension, congestive heart failure, glomerulopaty, tubulointestitial disorders, renal failure, angiostenosis, or cerebrovascular disorders, such as cerebral apoplexy. In a further embodiment of the present invention the compounds and compositions of 30 the present invention are useful for the treatment and/or prophylaxis of hematopoetic disorders and their consecutive complications and disorders such as acute myeloid leukemia (AML), Morbus Hodgkin, Non-Hodgkin's lymphoma; hematopoetic disease, acute no n-lymphocytic leukemia (ANILL), myeloproliferative disease acute 3 WO 2011/104340 PCT/EP2011/052813 promyelocytic leukemia (APL), acute myelomonocytic leukemia (AMMoL), multiple myeloma, polycythemia vera, lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CCL), Wilm's tumor, or Ewing's Sarcoma. In a further embodiment of the present invention the compounds and compositions of 5 the present invention are useful for the treatment and/or prophylaxis of cancer and consecutive complications and disorders such as cancer of the upper gastrointestinal tract, pancreatic carcinoma, breast cancer, colon cancer, ovarian carcinoma, cervix carcinoma, endometrial cancer, brain tumor, testicular cancer, laryngeal carcinoma, osteocarcinoma, prostatic cancer, retinoblastoma, liver carcinoma, lung cancer, 10 neuroblastoma, renal carcinoma, thyroid carcinoma, esophageal cancer, soft tissue sarcoma, skin cancer, osteosarcoma, rhabdomyosarcoma, bladder cancer, metastatic cancer, cachexia, or pain. Certain anti-cancer drugs such as cisplatin are linked to serious side effects such as 15 nephrotoxicity or ototoxicity, which can be dose limiting. Activation of Mnks has been linked to these side effects. In a further embodiment of the present invention, the compounds and compositions of the present invention are useful for the treatment and/or prophylaxis of ear or kidney damage, in particular for the prevention or treatment of ear and kidney drug induced damage 20 Furthermore, the present invention relates to the use of thienopyrimidine compounds for the production of pharmaceutical compositions for the prophylaxis and/or therapy of cytokine related diseases. 25 Such diseases are i.a. inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, neurodegenerative diseases, allergies, or other conditions associated with proinflammatory cytokines. Allergic and inflammatory diseases such as acute or chronic inflammation, chronic 30 inflammatory arthritis, rheumatoid arthritis, psoriasis, COPD, inflammatory bowel disease, asthma and septic shock and their consecutive complications and disorders associated therewith. 4 WO 2011/104340 PCT/EP2011/052813 Inflammatory diseases like rheumatoid arthritis, inflammatory lung diseases like COPD, inflammatory bowel disease and psoriasis afflict one in three people in the course of their lives. Not only do those diseases impose immense health care costs, but also they are often crippling and debilitating. 5 Although inflammation is the unifying pathogenic process of these inflammatory diseases below, the current treatment approach is complex and is generally specific for any one disease. Many of the current therapies available today only treat the symptoms of the disease and not the underlying cause of inflammation. 10 The compositions of the present invention are useful for the treatment and/or prophylaxis of inflammatory diseases and consecutive complications and disorders. such as chronic or acute inflammation, inflammation of the joints such as chronic inflammatory arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, juvenile 15 rheumatoid arthritis, Reiter's syndrome, rheumatoid traumatic arthritis, rubella arthritis, acute synovitis and gouty arthritis; inflammatory skin diseases such as sunburn, psoriasis, erythrodermic psoriasis, pustular psoriasis, eczema, dermatitis, acute or chronic graft formation, atopic dermatitis, contact dermatitis, urticaria and scleroderma; inflammation of the gastrointestinal tract such as inflammatory bowel 20 disease, Crohn's disease and related conditions, ulcerative colitis, colitis, and diverticulitis; nephritis, urethritis, salpingitis, oophoritis, endomyometritis, spondylitis, systemic lupus erythematosus and related disorders, multiple sclerosis, asthma, meningitis, myelitis, encephalomyelitis, encephalitis, phlebitis, thrombophlebitis, respiratory diseases such as asthma, bronchitis, chronic obstructive pulmonary 25 disease (COPD), inflammatory lung disease and adult respiratory distress syndrome, and allergic rhinitis; endocarditis, osteomyelitis, rheumatic fever, rheumatic pericarditis, rheumatic endocarditis, rheumatic myocarditis, rheumatic mitral valve disease, rheumatic aortic valve disease, prostatitis, prostatocystitis, spondoarthropathies ankylosing spondylitis, synovitis, tenosynovotis, myositis, 30 pharyngitis, polymyalgia rheumatica, shoulder tendonitis or bursitis, gout, pseudo gout, vasculitides, inflammatory diseases of the thyroid selected from granulomatous thyroiditis, lymphocytic thyroiditis, invasive fibrous thyroiditis, acute thyroiditis; Hashimoto's thyroiditis, Kawasaki's disease, Raynaud's phenomenon, Sjogren's 5 WO 2011/104340 PCT/EP2011/052813 syndrome, neuroinflammatory disease, sepsis, conjunctivitis, keratitis, iridocyclitis, optic neuritis, otitis, lymphoadenitis, nasopaharingitis, sinusitis, pharyngitis, tonsillitis, laryngitis, epiglottitis, bronchitis, pneumonitis, stomatitis, gingivitis. oesophagitis, gastritis, peritonitis, hepatitis, cholelithiasis, cholecystitis, glomerulonephritis, 5 goodpasture's disease, crescentic glomerulonephritis, pancreatitis, endomyometritis, myometritis, metritis, cervicitis, endocervicitis, exocervicitis, parametritis, tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis, pneumoconiosis, pyresis, inflammatory polyarthropathies, psoriatric arthropathies, intestinal fibrosis, bronchiectasis and enteropathic arthropathies. 10 Moreover, cytokines are also believed to be implicated in the production and development of various cardiovascular and cerebrovascular disorders such as congestive heart disease, myocardial infarction, the formation of atherosclerotic plaques, hypertension, platelet aggregation, angina, stroke, Alzheimer's disease, 15 reperfusion injury, vascular injury including restenosis and peripheral vascular disease, and, for example, various disorders of bone metabolism such as osteoporosis (including senile and postmenopausal osteoporosis), Paget's disease, bone metastases, hypercalcaemia, hyperparathyroidism, osteosclerosis, osteoporosis and periodontitis, and the abnormal changes in bone metabolism which 20 may accompany rheumatoid arthritis and osteoarthritis. Excessive cytokine production has also been implicated in mediating certain complications of bacterial, fungal and/or viral infections such as endotoxic shock, septic shock and toxic shock syndrome and in mediating certain complications of 25 CNS surgery or injury such as neurotrauma and ischaemic stroke. Excessive cytokine production has, moreover, been implicated in mediating or exacerbating the development of diseases involving cartilage or muscle resorption, pulmonary fibrosis, cirrhosis, renal fibrosis, the cachexia found in certain chronic 30 diseases such as malignant disease and acquired immune deficiency syndrome (AIDS), tumour invasiveness and tumour metastasis and multiple sclerosis. The treatment and/or prophylaxis of these diseases are also contemplated by the present invention 6 WO 2011/104340 PCT/EP2011/052813 Additionally, the inventive compositions may be used to treat inflammation associated with autoimmune diseases including, but not limited to, systemic lupus erythematosis, Addison's disease, autoimmune polyglandular disease (also known as 5 autoimmune polyglandular syndrome), glomerulonephritis, rheumatoid arthritis scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, glomerulonephritis, rheumatoid arthritis autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, 10 Crohn's disease, psoriasis, and graft vs. host disease. In a further embodiment the compositions of the present invention may be used for the treatment and prevention of infectious diseases such as sepsis, septic shock, Shigellosis, and Helicobacter pylori and viral diseases including herpes simplex type 15 1 (HSV-1), herpes simplex type 2 (HSV-2), cytomegalovirus, Epstein-Barr, human immunodeficiency virus (HIV), acute hepatitis infection (including hepatitis A, hepatits B, and hepatitis C), HIV infection and CMV retinitis, AIDS or malignancy, malaria, mycobacterial infection and meningitis. These also include viral infections, by influenza virus, varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 20 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), Poxvirus, Vacciniavirus, Monkeypoxvirus, pseudorabies and rhinotracheitis. The compositions of the present invention may also be used topically in the treatment or prophylaxis of topical disease states mediated by or exacerbated by excessive 25 cytokine production, such as inflamed joints, eczema, psoriasis and other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation. Periodontal disease has also been implemented in cytokine production, both topically 30 and systemically. Hence, use of compositions of the present invention to control the inflammation associated with cytokine production in such peroral diseases such as gingivitis and periodontitis is another aspect of the present invention. Finally, the compositions of the present invention may also be used to treat or 7 WO 2011/104340 PCT/EP2011/052813 prevent neurodegenerative disease selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, frontotemporal lobar dementia, spinocerebellar ataxia, dementia with Lewy bodies, cerebral ischemia or neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity or 5 hypoxia. In a preferred embodiment the compositions of the present invention may be used to treat or prevent a disease selected from chronic or acute inflammation, chronic inflammatory arthritis, rheumatoid arthritis, psoriasis, COPD, inflammatory bowel 10 disease, septic shock, Crohn's disease, ulcerative colitis, multiple sclerosis and asthma. Protein kinases are important enzymes involved in the regulation of many cellular functions. The LK6-serine/threonine-kinase gene of Drosophila melanogaster was 15 described as a short-lived kinase which can associate with microtubules (J. Cell Sci. 1997, 110(2): 209-219). Genetic analysis in the development of the compound eye of Drosophila suggested a role in the modulation of the RAS signal pathway (Genetics 2000 156(3): 1219-1230). The closest human homologues of Drosophila LK6-kinase are the MAP-kinase interacting kinase 2 (Mnk2, e.g. the variants Mnk2a and Mnk2b) 20 and MAP-kinase interacting kinase 1 (Mnk1) and variants thereof. These kinases are mostly localized in the cytoplasm. Mnks are phosphorylated by the p42 MAP kinases Erk1 and Erk2 and the p38-MAP kinases. This phosphorylation is triggered in a response to growth factors, phorbol esters and oncogenes such as Ras and Mos, and by stress signaling molecules and cytokines. The phosphorylation of Mnk 25 proteins stimulates their kinase activity towards eukaryotic initiation factor 4E (eIF4E) (EMBO J. 16: 1909-1920, 1997; Mol Cell Biol 19, 1871-1880, 1990; Mol Cell Biol 21, 743-754, 2001). Simultaneous disruption of both, the Mnk1 and Mnk2 gene in mice diminishes basal and stimulated eIF4E phosphorylation (Mol Cell Biol 24, 6539-6549, 2004). Phosphorylation of eIF4E results in a regulation of the protein translation (Mol 30 Cell Biol 22: 5500-5511, 2001). There are different hypotheses describing the mode of the stimulation of the protein translation by Mnk proteins. Most publications describe a positive stimulatory effect 8 WO 2011/104340 PCT/EP2011/052813 on the cap-dependent protein translation upon activation of MAP kinase-interacting kinases. Thus, the activation of Mnk proteins can lead to an indirect stimulation or regulation of the protein translation, e.g. by the effect on the cytosolic phospholipase 2 alpha (BBA 1488:124-138, 2000). 5 WO 03/037362 discloses a link between human Mnk genes, particularly the variants of the human Mnk2 genes, and diseases which are associated with the regulation of body weight or thermogenesis. It is postulated that human Mnk genes, particularly the Mnk2 variants are involved in diseases such as e.g. metabolic diseases including 10 obesity, eating disorders, cachexia, diabetes mellitus, hypertension, coronary heart disease, hypercholesterolemia, dyslipidemia, osteoarthritis, biliary stones, cancer of the genitals and sleep apnea, and in diseases connected with the ROS defense, such as e.g. diabetes mellitus and cancer. WO 03/03762 moreover discloses the use of nucleic acid sequences of the MAP kinase-interacting kinase (Mnk) gene family 15 and amino acid sequences encoding these and the use of these sequences or of effectors of Mnk nucleic acids or polypeptides, particularly Mnk inhibitors and activators in the diagnosis, prophylaxis or therapy of diseases associated with the regulation of body weight or thermogenesis. 20 WO 02/103361 describes the use of kinases 2a and 2b (Mnk2a and Mnk2b) interacting with the human MAP kinase in assays for the identification of pharmacologically active ingredients, particularly useful for the treatment of diabetes mellitus type 2. Moreover, WO 02/103361 discloses also the prophylaxis and/or therapy of diseases associated with insulin resistance, by modulation of the 25 expression or the activity of Mnk2a or Mnk2b. Apart from peptides, peptidomimetics, amino acids, amino acid analogues, polynucleotides, polynucleotide analogues, nucleotides and nucleotide analogues, 4-hydroxybenzoic acid methyl ester are described as a substance which binds the human Mnk2 protein. 30 First evidence for a role of Mnks in inflammation was provided by studies demonstrating activation of Mnk1 by proinflammatory stimuli. The cytokines TNFa and IL-1p trigger the activation of Mnk1 in vitro (Fukunaga and Hunter, EMBO J 16(8): 1921-1933, 1997) and induce the phosphorylation of the Mnk-specific 9 WO 2011/104340 PCT/EP2011/052813 substrate eIF4E in vivo (Ueda et al., Mol Cell Biol 24(15): 6539-6549, 2004). In addition, administration of lipopolysaccharide (LPS), a potent stimulant of the inflammatory response, induces activation of Mnk1 and Mnk2 in mice, concomitant with a phosphorylation of their substrate eIF4E (Ueda et al., Mol Cell Biol 24(15): 5 6539-6549, 2004). Furthermore, Mnk1 has been shown to be involved in regulating the production of proinflammatory cytokines. Mnk1 enhances expression of the chemokine RANTES (Nikolcheva et al., J Clin Invest 110, 119-126, 2002). RANTES is a potent 10 chemotractant of monocytes, eosinophils, basophiles and, natural killer cells. It activates and induces proliferation of T lymphocytes, mediates degranulation of basophils and induces the respiratory burst in eosinophils (Conti and DiGioacchino, Allergy Asthma Proc 22(3):133-7, 2001) 15 WO 2005/00385 and Buxade et al., Immunity 23: 177-189, August 2005 both disclose a link between Mnks and the control of TNFa biosynthesis. The proposed mechanism is mediated by a regulatory AU-rich element (ARE) in the TNFa mRNA. Buxade et al. demonstrate proteins binding and controlling ARE function to be phosphorylated by Mnkl and Mnk2. Specifically Mnk-mediated phosphorylation of 20 the ARE-binding protein hnRNP Al has been suggested to enhance translation of the TNFa mRNA. TNFa is not the only cytokine regulated by an ARE. Functional AREs are also found in the transcripts of several interleukins, interferones and chemokines (Khabar, J 25 Interf Cytokine Res 25: 1-10, 2005). The Mnk-mediated phosphorylation of ARE binding proteins has thus the potential to control biosynthesis of cytokines in addition to that of TNFa. Current evidence demonstrates Mnks as down stream targets of inflammatory 30 signalling as well as mediators of the inflammatory response. Their involvement in the production of TNFa, RANTES, and potentially additional cytokines suggests inhibition of Mnks as strategy for anti-inflammatory therapeutic intervention. 10 WO 2011/104340 PCT/EP2011/052813 Mnk1 and Mnk2 (including all splice forms) phosphorylate the translation factor eIF4E on Serine 209. Mnk1/2 double knockout mice completely lack phosphorylation on Serine 209, indicating that Mnk kinase are the only kinases able to phosphorylate this site in vivo (Ueda et al., Mol Cell Biol. 2004; 24(15):6539-49). eIF4E is 5 overexpressed in a wide range of human malignancies, and high eIF4E expression is frequently associated with more aggressive disease and poor prognosis. Furthermore, eIF4E can act as an oncogene when assayed in standard assays for oncogenic activity (e.g. Ruggero et al., Nat Med. 2004 May;10(5):484-6). eIF4E excerts its oncogenic activity by stimulating the translation of oncogenes such as c 10 myc and cyclinD1 (Culjkovic et al., J Cell Biol. 2006; 175(3):415-26), by increasing the expression of pro-survival factors such as MCP-1 (Wendel et al., Genes Dev. 2007; 21(24):3232-7) and by positively regulating pathways of drug resistance (Wendel et al., Nature 2004; 428(6980):332-7; Graff et el., Cancer Res. 2008; 68(3):631-4; De Benedetti and Graff, Oncogene 2004; 23(18):3189-99; Barnhart and 15 Simon, J Clin Invest. 2007; 117(9):2385-8). Suppression of eIF4E expression by antisense oligonucleotides has shown promise in preclinical experiments with human tumor cells (Graff et al., J Clin Invest. 2007; 117(9):2638-48). It has been shown that phosphorylation on Ser209 is strictly required for the oncogenic activity of eIF4E in vitro and in vivo (Topisirovic et al., Cancer Res. 2004; 64(23):8639-42; Wendel et al., 20 Genes Dev. 2007; 21(24):3232-7). Thus, inhibition of Mnk1 and Mnk2 is expected to have beneficial effects in human malignancies. Inhibitors of Mnk (referred to as CGP57380 and CGP052088) have been described (cf. Mol. Cell. Biol. 21, 5500, 2001; Mol Cell Biol Res Comm 3, 205, 2000; Genomics 69, 63, 2000). CGP052088 is a staurosporine derivative having an IC 50 of 70 nM for 25 inhibition of in vitro kinase activity of Mnk1. CGP57380 is a low molecular weight selective, non-cytotoxic inhibitor of Mnk2 (Mnk2a or Mnk2b) or of Mnk1: The addition of CGP57380 to cell culture cells, transfected with Mnk2 (Mnk2a or Mnk2b) or Mnk1 showed a strong reduction of phosphorylated eIF4E. 30 Further inhibitors of Mnk have been described. See for example Applicants patent applications WO 06/066937, describing pyrazolopyrimidine compounds, WO 06/136402 describing certain thienopyrimidine compounds, WO 07/115822 11 WO 2011/104340 PCT/EP2011/052813 describing further thienopyrimidine compounds with modified core ring, and WO 08/006547 describing pyrrolopyrimidines as inhibitors of Mnk kinases. The problem underlying the present invention is to provide potent and selective Mnk1 5 and/or Mnk2 inhibitors which may effectively and safely be used for the treatment of metabolic diseases, inflammatory diseases, cancer, neurodegenerative diseases and their consecutive complication and disorders. It has now been surprisingly found that certain thienopyrimidine compounds are 10 potent inhibitors of the kinase enzymes Mnk1 and/or Mnk2 and/or variants thereof and as such may be useful in the prophylaxis and/or therapy of diseases which can be influenced by the inhibition of the kinase activity of Mnk1 and/or Mnk2 (Mnk2a or Mnk2b) and/or variants thereof. 15 In contrast to the thienopyrimidine compounds known in the art, for example, the compoonds disclosed in the Applicants patent applications WO 06/136402 and WO 2007/115822, the thienopyrimidine compounds of the present invention provide several advantages, namely, enhanced solubility, the possibility to form stable salts, improved metabolic stability, improved pharmacokinetic properties, enhanced or 20 retained activity in biochemical or cellular Mnk activity assays and enhanced or retained selectivity against other kinases. The thienopyrimidine compounds disclosed in WO 06/136402 and WO 07/115822 exhibit high activity in Mnk enzyme assays and extremely high selectivity, however 25 they show a very low solubility and are in most cases metabolic unstable resulting in undesired pharmacokinetic properties. It has been surprisingly found that by the introduction of a polar group at the R 4 position in the compounds of general formula (1) below leads to surprising substantial 30 metabolic stabilization, rendering the thienopyrimidines of the present invention useful for in vivo pharmacological applications. Moreover, compounds described in this application also show improved solubility, 12 WO 2011/104340 PCT/EP2011/052813 have strong inhibitory potency in biochemical and cellular assays and are highly selective, resulting in overall greatly improved pharmacological properties. If not specified otherwise, any alkyl moiety mentioned in this application may be 5 straight-chained or branched. Thienopyrimidine compounds of the present invention are compounds of the general formula (1): R1 x 11R NH R3 N N S 10 wherein X is CH or N,

R

1 is a hydrogen or halogen atom or CN or an C1.3 alkyl or CONH 2 group, 15

R

2 is a straight-chained or branched C1.

6 alkyl group which is independently substituted with one or two fluorine atoms, or one or two trifluoromethyl, tetrahydropyranyl, cyclopropyl, H 2 N-CO-, R 5 NHCO- or (R 5

)

2 N-CO- groups, 20 wherein the above-mentioned cyclopropyl group may be substituted with one or two F or -CH 2 -CN, and wherein the two R5 groups together with the N atom to which they are attached may form a 4- to 8-membered ring, in which a carbon atom may be 25 replaced by a 0, S, SO, SO 2 and/or which may be substituted with OH, NH 2 ,

N(C

1

.

3 -alkyl) 2 , NH(C 1

.

3 alkyl), CF 3 or C1.

3 -alkyl, 13 WO 2011/104340 PCT/EP2011/052813 or a straight-chained or branched C 2

-

6 alkyl group which is independently substituted in position 2 to 6 with one or two hydroxy, C1-3 alkoxy, amino, CN, R 5 NH-, (R 5

)

2 N-,

R

5 0CONH-, R 5 CONH-, R 5

SO

2 NH-, R 5 NHCONH- groups, 5 wherein R 5 is a C 1

.

5 alkyl group, preferably a C 1 .4 alkyl group, more preferably Me, i-Pr or t-Bu, each optionally substituted with one CF 3 , NH 2 , NH(C 1

.

3 alkyl),

N(C

1 .3.alkyl) 2 or MeO- group, and wherein the hydrogen atoms of any of the above-mentioned NH moiety may be replaced by methyl, 10

R

3 is a C 1 -2alkyl group and

R

4 is a carboxy, C1.3 alkoxy-carbonyl, -CONH 2 , -CONHR 7 , -CONH-OR 7 , -CONH S0 2

R

7 or -CO-NH-L-R 6 group, 15 wherein L is a -(CH 2 )n-, -CH 2

-C-C-CH

2 -, or

R

6 is OH, -NH 2 , -NHR 7 , -N(R 7

)

2 , -NH-C0 2

R

7 or a 3- to 6-membered cyclic amine such as pyrrolidine or piperidine, 20 n is2or3and

R

7 is C1.

4 alkyl, preferably methyl, or a tautomer, enantiomer or salt thereof. 25 Preferred compounds of formula (I) are those, wherein X, R 1 , R 2 and R4 are as defined above and 30 R 3 is methyl, or a tautomer or salt thereof. 14 WO 2011/104340 PCT/EP2011/052813 A preferred subgroup concerns those compound of formula (1), wherein

R

2 to R 4 are as defined as above, 5 X is CH and

R

1 is a fluorine atom, 10 or a tautomer or salt thereof. Another preferred subgroup concerns those compounds of formula (1), wherein

R

2 to R 4 are as defined above, 15 X is N and

R

1 is a hydrogen atom, 20 or a tautomer or salt thereof. A third preferred subgroup concerns those compounds of formula (1), wherein X, R 1 , R 3 and R4 are as defined above and 25 R 2 is selected from: (dimethylamino)-carbonylmethyl, ethyl, 2-amino-ethyl, 1-(trifluoromethyl)-ethyl; isopropyl optionally substituted in position 2 with ethoxycarbonyl, amino or tert butyloxycarbonylamino; 30 2,2'-diamino-isopropyl, 2,2'-difluoro-isopropyl, 2,2'-di-(ethoxy)-isopropyl, 2,2'-bis (tert-butyloxycarbonylamino)-isopropyl, 2-[2'-(trifluoromethyl)-ethylamino]-isopropyl, 3-amino-1-methyl-propyl, 3-(dimethylamino)-1-methyl-propyl, 3-hydroxy-1,3-dimethyl-butyl, or 15 WO 2011/104340 PCT/EP2011/052813 a fluor-containing residue such as 1,3-difluoropropan-2-yl, 1,1,1-trifluoropropan-2-yl or 1,1-difluoroethyl-, or a tautomer or salt thereof, 5 particularly those compounds of formula (1), wherein X, R 1 , R 3 and R4 are as defined above and

R

2 is selected from: isopropyl and isobutyl optionally substituted in position 2 or 3 with ethoxycarbonyl, 10 amino, tert-butyloxycarbonylamino or methylsulfonylamino or a tautomer or salt thereof. A fourth preferred subgroup concerns those compounds of formula (1), wherein X, R 1 to R 3 are as defined above and 15 R4 is selected from: carboxy, C1-3 alkoxy-carbonyl, aminocarbonyl, N-(C 1 3 alkyl)-aminocarbonyl or N,N [di-(C 1

.

3 alkyl)]-aminocarbonyl group, wherein the alkyl moiety of the above-mentioned N-(C 1 3 alkyl)-aminocarbonyl 20 and N,N-[di-(C 1 .3 alkyl)]-aminocarbonyl groups may optionally be terminally substituted with a hydroxy, amino, N-(C 1 .3 alkyl)-amino or N,N-[di-(C 1 .3 alkyl)] amino group, or a tautomer or salt thereof, 25 particularly those compounds of formula (1), wherein X, R 1 to R 3 are as defined above and

R

4 is selected from: aminocarbonyl, N-methyl-aminocarbonyl; 30 N-ethyl-aminocarbonyl terminally substituted in the ethyl moiety with hydroxy or N,N dimethylamino; N-(n-propyl)-aminocarbonyl terminally substituted in the n-propyl moiety with N,N dimethylamino; 16 WO 2011/104340 PCT/EP2011/052813 Carboxy or methoxycarbonyl, or a tautomer or salt thereof. 5 Particularly preferred Compounds of formula (I) are: a) Methyl 4-(2-(1-aminopropan-2-yloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3 d]pyrimidine-6-carboxylate, b) 4-(2-(1 -Aminopropan-2-yloxy)-4-fluorophenylamino)-N-5-methylthieno[2,3 10 d]pyrimidine-6-carboxamide, c) Methyl 4-(4-fluoro-(2-(1-methylsulfonamido)propan-2-yloxy)phenylamino)-5 methyl-th ieno[2,3-d]pyrimid ine-6-carboxylate, 15 d) 4-(2-(1 -Aminopropan-2-yloxy)-4-fluorophenylamino)-5-methylthieno[2,3 d]pyrimid ine-6-carboxamide, e) 4-(2-(1 -Aminopropan-2-yloxy)-4-fluorophenylamino)-5-methy-Ithieno[2,3 d]pyrimidine-6-carboxylic acid, 20 f) Methyl 4-(2-(4-aminobutan-2yloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3 d]pyrimidine-6-carboxylate, g) Methyl 4-(4-fluoro-2-(4-(methylsulfonamido)butan-2yloxy)phenylamino)-5-methyl 25 thieno[2,3-d]pyrimidine-6-carboxylate , h) 4-(2-(4-Aminobutan-2yloxy)pyridin-3ylamino)-5-methylthieno[2,3-d]pyrimidine-6 carboxylate, 30 i) N-(3-(Dimethylamino)propyl)-4-(4-fluoro-2-(4-hydroxy-4-methylpentan-2 yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxamide, 17 WO 2011/104340 PCT/EP201 1/052813 j) 5-Methyl-4-(2-(1 ,1,1 -trifluoropropan-2yloxy)pyridin-3-ylamino)thieno[2,3 d]pyrimidine-6-carboxylic acid, k) 5-Methyl-4-(2-(1 ,1,1 -trifluoropropan-2yloxy)pyridin-3-ylamino)thieno[2,3 5 d] pyri mid ine-6-carboxamide, 1) N-Methyl- 5-methyl-4-(2-(1 ,1,1 trifluoropropan-2-yloxy)pyridin-3-ylamino)thieno[2,3 d] pyri mid i ne-6-N-methyl carboxamide, 10 m) 4-(2-(1 ,3-Difluoropropan-2-yloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3 d] pyri mid i ne-6-carboxamide, n) N-Methyl-4-(2-(1 ,3-difluoropropan-2-yloxy)-4-fluorophenylamino) 5-methyl -th ieno[2,3d]pyri mid i ne-6-carboxamide, 15 o) 4-(2-(1 ,3-Difluoropropan-2-yloxy)-4-fluorophenylamino)-N-(3 (d i methyl ami no)propyl)-5-methyl-th ieno[2,3-d]-pyri mid i ne-6-carboxamide, p) 4-(2-(1 ,3-Difluoropropan-2-yloxy)-4-fluorophenylamino) 20 N-(2-(dimethylamino)ethyl)-5-methylthieno[2,3-d] pyrimidine-6-carboxamide, q) 4-(2-(1 ,3-Difluoropropan-2-yloxy)-4-fluorophenylamino)-N-(2-(hydroxyethyl)-5 methylthieno[2,3-d] pyri mid ine-6-carboxamide, 25 r) 4-(2-(1 ,3-Difluoropropan-2-yloxy)-4-fluorophenylamino)-5-methyl-N-(3-(pyrrolidin-1 yI )propyl )th ieno[2,3-d] pyri mid i ne-6-carboxa mide, s) N-((trans)-2-Aminocyclopropyl)-4-(2-(1 ,3-difluoropropan-2-yloxy)-4 fi uorophenylamino)-5-methylthieno[2,3-d]pyrimid ine-6-carboxamide, 30 t) 4-(2-(2-Fluoropropoxy)pyridin-3-ylamino)-N-(2-hydroxyethyl)-5-methylthieno[2,3 d] pyri mid i ne-6-carboxamide, 18 WO 2011/104340 PCT/EP2011/052813 u) 4-(2-(2,2-Difluoroethoxy)pyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6 carboxylic acid, v) 4-(2-(2,2-Difluoroethoxy)pyridin-3-ylamino)-5-methyl-thieno[2,3-d]pyrimidine-6 5 carboxamide, w) 4-(2-(2,2-Difluoroethoxy)pyridin-3-ylamino)-N-(3-(dimethylamino)propyl)-5 methylth ieno[2,3-d]pyrimidine-6-carboxamide, 10 x) 4-(2-(1 -(Ethylamino)-1 -oxopropan-2-yloxy)-4-fluorophenylamino)-N,5 dimethylthieno[2,3-d]pyrimidine-6-carboxamide and y) 4-(2-(1 -(Ethylamino)-1 -oxopropan-2-yloxy)-4-fluorophenylamino)-N,5 d imethylthieno[2,3-d]pyrimidine-6-carboxamide, 15 or a pharmaceutically acceptable salt thereof. Typical methods of preparing the compounds of the invention are described below in the experimental section. 20 The potent inhibitory effect of the compounds of the invention may be determined by in vitro enzyme assays as described in the Examples in more detail. The compounds of the present invention can be synthesized according to the following synthesis schemes: 25 19 WO 2011/104340 PCT/EP2011/052813 R1 X O-R2 R1 X F catalyst + + R2 base H 2 I - 0 0 A B C R1 X O-R2 X =CH, N N D Compounds of the general formula C can be synthesized by reaction of a compound A with the deprotonated alcohol B in appropriate solvents such as THF or DMF at a temperature between 0 OC and 150 C. The deprotonated form of B can be obtained 5 by deprotonation with a base such as sodium hydride or lithium hexamethyldisilazane at a preferred temperature of 0 C. Hydrogenation of compound C in order to obtain a compound of the general formula D can be achieved by reacting C in the presence of hydrogen and a catalyst such as palladium or Raney nickel. The hydrogen can be introduced as a gas or stem from a hydrogen source such as ammonium formate. R1 X O-R2 RR2 Mitsunobu reaction N X = CH, N N I 0 10 E B C Compounds of the general formula C can be also obtained by Mitsunobu reaction of a compound with the general formula E with an alcohol B in the presence of triphenylphosphine and an dial kylazodicarboxylate such as diethylazodicarboxylate, diisopropylazodicarboxylate or di-tert.butylazodiacarboxylate in a solvent such as 15 THF at temperatures between -10 0C and 80 0C, preferrably between 0 0C and 30 0C. 20 WO 2011/104340 PCT/EP2011/052813 R1 X O-R2 CI R3 R 1 X O-R2 R N R3 N R3 -R " 3 " + N O-R Nk N S 0 o F G Ri X O-R2 Ri X O-R2 N R3 N-R" N R3 R N~ 0 N~ N-R" kN S 0 N S 0 X CH, N A compound of the formula G can be synthesized by reaction of compound D with F preferably in the presence of an acid such as p-toluene sulfonic acid or hydrochloric 5 acid in solvents such as dioxan at temperatures between 10 0C and 150 OC. Synthesis of a compound with the general formula H can be achieved by reaction of compound G with a base such as sodium hydroxide or lithium hydroxide in solvents such as methanol, ethanol, THF and water or mixtures thereof, preferably in ethanol/THF or THF/water at temperatures between 10 0C and 100 C. A compound 10 of the general formula J can be obtained by reaction of compound H with amines of the general formula I using amide coupling procedures employing reagents such as TBTU, HATU or EDC/ N-Hydroxysuccinimide in the presence or absence of bases such as diisopropylethylamine in solvents such as DMF or THF at temperatures between 0 C and 120 C preferably between 0 C and 30 C. 15 Pharmaceutically acceptable salts of the compounds of the invention of formula (1) can be formed with numerous organic and inorganic acids and bases. Exemplary acid addition salts including acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, 20 camphersulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethane sulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, 21 WO 2011/104340 PCT/EP2011/052813 hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane sulfonate, lactate, maleate, methane sulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenyl sulfonate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, sulfonate, 5 tartrate, thiocyanate, toluene sulfonate such as tosylate, undecanoate, or the like. Basic nitrogen-containing moieties can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromide and iodide; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long-chain alkyl 10 halides such as decyl, lauryl, myristyl and stearyl chloride, bromide and iodide, or aralkyl halides like benzyl and phenethyl bromides, or others. Water soluble or dispersible products are thereby obtained. Pharmaceutically acceptable basic addition salts include but are not limited to cations based on the alkaline and alkaline earth metals such as sodium, lithium, potassium, 15 calcium, magnesium, aluminum salts and the like, as well as non toxic ammonium quarternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. Other representative amines useful for the formation of base addition salts include benzazethine, dicyclohexyl 20 amine, hydrabine, N-methyl-D-glucamine, N-methyl-D-glucamide, t-butyl amine, diethylamine, ethylendiamine, ethanolamine, diethanolamine, piperazine and the like and salts with amino acids such as arginine, lysine, or the like. Unless specifically indicated, throughout the specification and the appended claims, 25 a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc...) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including 30 pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound. 22 WO 2011/104340 PCT/EP2011/052813 As used herein the term "metabolite" refers to (i) a product of metabolism, including intermediate and products, (ii) any substance involved in metabolism (either as a product of metabolism or as necessary for metabolism), or (iii) any substance produced or used during metabolism. In particular it refers to the end product that 5 remains after metabolism. As used herein the term "prodrug" refers to (i) an inactive form of a drug that exerts its effects after metabolic processes within the body convert it to a usable or active form, or (ii) a substance that gives rise to a pharmacologically active metabolite, 10 although not itself active (i.e. an inactive precursor). The terms "prodrug" or "prodrug derivative" mean a covalently-bonded derivative or carrier of the parent compound or active drug substance which undergoes at least some biotransformation prior to exhibiting its pharmacological effect(s). In general, 15 such prodrugs have metabolically cleavable groups and are rapidly transformed in vivo to yield the parent compound, for example, by hydrolysis in blood, and generally include esters and amide analogs of the parent compounds. The prodrug is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, 20 improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity). In general, prodrugs themselves have weak or no biological activity and are stable under ordinary conditions. Prodrugs can be readily prepared from the parent compounds using methods known in the art, such as those described in A Textbook of Drug Design and Development, 25 Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, particularly Chapter 5: "Design and Applications of Prodrugs"; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, K.B. Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985, particularly pp. 309-396; Burger's Medicinal Chemistry and 30 Drug Discovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995, particularly Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as Novel Delivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975; Bioreversible Carriers in Drug Design, 23 WO 2011/104340 PCT/EP2011/052813 E.B. Roche (ed.), Elsevier, 1987, each of which is incorporated herein by reference in their entireties. The term "pharmaceutically acceptable prodrug" as used herein means a prodrug of 5 a compound of the invention which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible. 10 As used herein the term "C3_10 cycloalkyl" or "C3_8 cycloalkyl" refers to mono- or polycyclic carbocyclic alkyl substituent or group having 3 to 10 or 3 to 8 ring atoms respectively, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, 15 cycloheptenyl, cycloheptadienyl, cycloheptatrienyl perhydrated naphthalene or indene, adamantyl or norbonanyl and the like. The term "C1_8 alkyl" as used herein alone or in combination with other terms such as in alkoxy refers to a C1_8, preferably C1_4 straight or branched alkyl/alkoxy group such as methyl, ethyl, propyl (iso-, n-), butyl (iso-, n-, sec-, tert-), pentyl, hexyl, methoxy, 20 ethoxy, propoxy (iso-, n-), butoxy (iso-, n-, sec-, tert-), pentoxy, hexoxy; moreover, the term "C1_8 alkyl" also includes an alkyl group which may contain oxygen in the chain and may be substituted with halogen to form an ether or halogenated ether group. 25 Any hydrogen atom, particularly in an alkyl, alkoxy or alkenyl group may be replaced by a fluorine atom. The term "C2-8 alkenyl" by itself or as part of another group refers to a straight or branched alkenyl group of 2 to 8 carbons, preferably 2 to 6 carbons, in the normal 30 chain, which include one or more double bonds in the normal chain, such as vinyl, 2 propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2 heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl. 24 WO 2011/104340 PCT/EP2011/052813 The term "heterocyclyl" refers to monocyclic saturated or unsaturated heterocyclyl groups with 1 to 4 hetero atoms selected from N, S and 0, with the remainder of the ring atoms being carbon atoms and having preferably a total number of ring atoms of 3 to 10, such as morpholino, piperazinyl, piperidinyl, pyridyl, pyrimidinyl, thiazolyl, 5 indolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyrazinyl, triazolyl, thiophenyl or furanyl. The term "heteroaryl" refers to a mono- or bicyclic aromatic group with 1 to 4 hetero atoms selected from N, S and 0, with the remainder of the ring atoms being carbon atoms and having preferably a total number of ring atoms of 5 to 10. Examples 10 without limitation of heteroaryl groups are such as benzofuranyl, furyl, thienyl, benzothienyl, thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyranyl, tetrahydropyranyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzoxazolyl, benzamidazolyl, indolyl, isoindolyl, pyrazinyl, diazinyl, pyrazine, triazinyltriazine, 15 tetrazinyl, tetrazolyl, benzothiophenyl, benzopyridyl and benzimidazolyl. In a further aspect the present invention provides pharmaceutical compositions comprising a thienopyrimidine compound of the present invention and optionally a pharmaceutically acceptable carrier. 20 The pharmaceutical composition according to the present invention may further comprise an additional therapeutic agent. Particularly preferred are compositions, wherein the additional therapeutic agent is selected from antidiabetics like insulin, long and short acting insulin analogues, sulfonylureas, biguanides, DPP-IV inhibitors, 25 SGLT2 inhibitors, 11 R-HSD inhibitors, glucokinase activators, AMPK activators, GIp 1 receptor agonists, GIP receptor agonists, DGAT inhibitors, PPARgamma agonists, PPARdelta agonists, and other antidiabetics derived from thiazolidinediones, lipid lowering agents such as statines, fibrates, ion exchange resins nicotinic acid derivatives, or HMG-CoA reductase inhibitors, cardiovascular therapeutics such as 30 nitrates, antihypertensiva such as P-blockers, ACE inhibitors, Ca-channel blockers, angiotensin II receptor antagonists, diuretics, thrombocyte aggregation inhibitors, or antineoplastic agents such as alkaloids, alkylating agents, antibiotics, or antimetabolites, or anti-obesity agents. Further preferred compositions are 25 WO 2011/104340 PCT/EP2011/052813 compositions wherein the additional therapeutic agent is selected from a histamine antagonist, a bradikinin antagonist, serotonin antagonist, leukotriene, an anti asthmatic, an NSAID, an antipyretic, a corticosteroid, an antibiotic, an analgetic, a uricosuric agent, chemotherapeutic agent, an anti gout agent, a bronchodilator, a 5 cyclooxygenase-2 inhibitor, a steroid, a 5-lipoxygenase inhibitor, an immunosuppressive agent, a leukotriene antagonist, a cytostatic agent, an antineoplastic agent, a mTor inhibitor, a Tyrosine kinase inhibitor, antibodies or fragments thereof against cytokines and soluble parts (fragments) of cytokine receptors. 10 More particularly preferred are compounds such as human NPH insulin, human lente or ultralente insulin, insulin Lispro, insulin Aspart, insulin Glulisine, insulin detemir or insulin Glargine, metformin, phenformin, acarbose, miglitol, voglibose, pioglitazone, rosiglizatone, rivoglitazone, aleglitazar, alogliptin, saxagliptin, sitagliptin, vildagliptin, 15 exenatide, liraglutide, albiglutide, pramlintide, carbutamide, chlorpropamide, glibenclamide (glyburide), gliclazide, glimepiride, glipizide, gliquidone, tolazamide, tolbutamide, atenolol, bisoprolol, metoprolol, esmolol, celiprolol, talinolol, oxprenolol, pindolol, propanolol, bupropanolol, penbutolol, mepindolol, sotalol, certeolol, nadolol, carvedilol, nifedipin, nitrendipin, amlodipin, nicardipin, nisoldipin, diltiazem, enalapril, 20 verapamil, gallopamil, quinapril, captopril, lisinopril, benazepril, ramipril, peridopril, fosinopril, trandolapril, irbesatan, losartan, valsartan, telmisartan, eprosartan, olmesartan, hydrochlorothiazide, piretanid, chlorotalidone, mefruside, furosemide, bendroflumethiazid, triamterene, dehydralazine, acetylsalicylic acid, tirofiban-HCI, dipyramidol, triclopidin, iloprost-trometanol, eptifibatide, clopidogrel, piratecam, 25 abciximab, trapidil, simvastatine, bezafibrate, fenofibrate, gemfibrozil, etofyllin, clofibrate, etofibrate, fluvastatine, lovastatine, pravastatin, colestyramide, colestipol HCl, xantinol nicotinat, inositol nicotinat, acipimox, nebivolol, glycerolnitrate, isosorbide mononitrate, isosorbide dinitrate, pentaerythrityl tetranitrate, indapamide, cilazepril, urapidil, eprosartan, nilvadipin, metoprolol, doxazosin, molsidormin, 30 moxaverin, acebutolol, prazosine, trapidil, clonidine, vinca alkaloids and analogues such as vinblastin, vincristin, vindesin, vinorelbin, podophyllotoxine derivatives, etoposid, teniposid, alkylating agents, nitroso ureas, N-lost analogues, cycloplonphamid, estamustin, melphalan, ifosfamid, mitoxantron, idarubicin, 26 WO 2011/104340 PCT/EP2011/052813 doxorubicin, bleomycin, mitomycin, dactinomycin, daptomycin, docetaxel, paclitaxel, carboplatin, cisplatin, oxaliplatin, BBR3464, satraplatin, busulfan, treosulfan, procarbazine, dacarbazine, temozolomide, chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, bendamustine, uramustine, ThioTEPA, 5 camptothecin, topotecan, irinotecan, rubitecan, etoposide, teniposide, cetuximab, panitumumab, trastuzumab, rituximab, tositumomab, alemtuzumab, bevacizumab, gemtuzumab, aminolevulinic acid, methyl aminolevulinate, porfimer sodium, verteporfin, axitinib, bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, vandetanib, retinoids 10 (alitretinoin, tretinoin), altretamine, amsacrine, anagrelide, arsenic trioxide, asparaginase (pegaspargase), bexarotene, bortezomib, denileukin diftitox, estramustine, ixabepilone, masoprocol, mitotane, testolactone, tipifarnib, abetimus, deforolimus, everolimus, gusperimus, pimecrolimus, sirolimus, tacrolimus, temsirolimus, antimetabolites such as cytarabin, fluorouracil, fluoroarabin, 15 gemcitabin, tioguanin, capecitabin, combinations such as adriamycin/daunorubicin, cytosine arabinosid/cytarabine, 4-HC, or other phosphamides. Other particularly preferred compounds are compounds such as clemastine, diphenhydramine, dimenhydrinate, promethazine, cetirizine, astemizole, 20 levocabastine, loratidine, terfenadine, acetylsalicylic acid, sodoum salicylate, salsalate, diflunisal, salicylsalicylic acid, mesalazine, sulfasalazine, osalazine, acetaminophen, indomethacin, sulindac, etodolac, tolmetin, ketorolac, bethamethason, budesonide, chromoglycinic acid, dimeticone, simeticone, domperidone, metoclopramid, acemetacine, oxaceprol, ibuprofen, naproxen, 25 ketoprofen, flubriprofen, fenoprofen, oxaprozin, mefenamic acid, meclofenamic acid, pheylbutazone, oxyphenbutazone, azapropazone, nimesulide, metamizole, leflunamide, eforicoxib, lonazolac, misoprostol, paracetamol, aceclofenac, valdecoxib, parecoxib, celecoxib, propyphenazon, codein, oxapozin, dapson, prednisone, prednisolon, triamcinolone, dexibuprofen, dexamethasone, flunisolide, 30 albuterol, salmeterol, terbutalin, theophylline, caffeine, naproxen, glucosamine sulfate, etanercept, ketoprofen, adalimumab, hyaluronic acid, indometacine, proglumetacine dimaleate, hydroxychloroquine, chloroquine, infliximab, etofenamate, auranofin, gold, [ 224 Ra]radium chloride, tiaprofenic acid, dexketoprofen(trometamol), 27 WO 2011/104340 PCT/EP2011/052813 cloprednol, sodium aurothiomalate aurothioglucose, colchicine, allopurinol, probenecid, sulfinpyrazone, benzbromarone, carbamazepine, lornoxicam, fluorcortolon, diclofenac, efalizumab, idarubicin, doxorubicin, bleomycin, mitomycin, dactinomycin, daptomycin, cytarabin, fluorouracil, fluoroarabin, gemcitabin, tioguanin, 5 capecitabin, adriamydin/daunorubicin, cytosine arabinosid/cytarabine, 4-HC, or other phosphamides, penicillamine, a hyaluronic acid preparation, arteparon, glucosamine, MTX, soluble fragments of the TNF-receptor (such as etanercept (Enbrel)) and antibodies against TNF (such as infliximab (Remicade), natalizumab (Tysabri) and adalimumab (Humira)). 10 It will be appreciated by the person of ordinary skill in the art that the compounds of the invention and the additional therapeutic agent may be formulated in one single dosage form, or may be present in separate dosage forms and may be either administered concomitantly (i.e. at the same time) or sequentially. 15 The pharmaceutical compositions of the present invention may be in any form suitable for the intended method of administration. The compounds of the present invention may be administered orally, parenterally, 20 such as bronchopulmonary, subcutaneously, intravenously, intramuscularly, intraperitoneally, intrathecally, transdermally, transmucosally, subdurally, locally or topically via iontopheresis, sublingually, by inhalation spray, aerosol or rectally and the like in dosage unit formulations optionally comprising conventional pharmaceutically acceptable excipients. 25 Excipients that may be used in the formulation of the pharmaceutical compositions of the present invention comprise carriers, vehicles, diluents, solvents such as monohydric alcohols such as ethanol, isopropanol and polyhydric alcohols such as glycols and edible oils such as soybean oil, coconut oil, olive oil, safflower oil 30 cottonseed oil, oily esters such as ethyl oleate, isopropyl myristate; binders, adjuvants, solubilizers, thickening agents, stabilizers, disintergrants, glidants, lubricating agents, buffering agents, emulsifiers, wetting agents, suspending agents, sweetening agents, colorants, flavors, coating agents, preservatives, antioxidants, 28 WO 2011/104340 PCT/EP2011/052813 processing agents, drug delivery modifiers and enhancers such as calcium phosphate, magnesium state, talc, monosaccharides, disaccharides, starch, gelatine, cellulose, methylcellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl B-cyclodextrin, polyvinylpyrrolidone, low melting waxes, ion exchange resins. 5 Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, 15 th Ed., Mack Publishing Co., New Jersey (1991). Dosage forms for oral administration include tablets, capsules, lozenges, pills, 10 wafers, granules, oral liquids such as syrups, suspensions, solutions, emulsions, powder for reconstitution. Dosage forms for parenteral administration include aqueous or olageous solutions or emulsions for infusion, aqueous or olageous solutions, suspensions or emulsions for 15 injection pre-filled syringes, and/or powders for reconstitution. Dosage forms for local/topical administration comprise insufflations, aerosols, metered aerosols, transdermal therapeutic systems, medicated patches, rectal suppositories, and/or ovula. 20 The amount of the compound of the present invention that may be combined with the excipients to formulate a single dosage form will vary upon the host treated and the particular mode of administration. 25 The pharmaceutical compositions of the invention can be produced in a manner known per se to the skilled person as described, for example, in Remington's Pharmaceutical Sciences, 15 th Ed., Mack Publishing Co., New Jersey (1991). In a further aspect of the invention the use of a thienopyrimidine compound of the 30 present invention for the production of a pharmaceutical composition for inhibiting the activity of the kinase activity of Mnk1 or Mnk2 (Mnk2a, Mnk2b) or further variants thereof is provided, in particular for the prophylaxis or therapy of metabolic diseases, hematopoietic disorders, cancer and their consecutive complications and disorders. 29 WO 2011/104340 PCT/EP2011/052813 Whereby the prophylaxis and therapy of metabolic diseases of the carbohydrate and/or lipid metabolism is preferred. Diseases of the invention that are influenced by the inhibition of the kinase activity of 5 Mnk1 and/or Mnk2 (Mnk2a or Mnk2b) and/or further variants thereof include diseases related to the regulation of metabolic diseases, such as obesity, eating disorders, cachexia, diabetes mellitus, metabolic syndrome, hypertension, coronary heart diseases, hypercholesterolemia, dyslipidemia, osteoarthritis, biliary stones and/or sleep apnea and diseases related to reactive oxygen compounds (ROS 10 defense) such as diabetes mellitus, neurodegenerative diseases and cancer. The pharmaceutical compositions of the invention are particularly useful for prophylaxis and treatment of obesity, diabetes mellitus and other metabolic diseases of the carbohydrate and lipid metabolism as stated above, in particular diabetes 15 mellitus and obesity. Thus in a more preferred embodiment of this invention the use of a thienopyrimidine compound for the production of a pharmaceutical composition for the prophylaxis or therapy of metabolic diseases is provided. 20 In yet a further aspect of the invention the use of a thienopyrimidine compound of the invention for the production of a pharmaceutical composition for treating or preventing a cytokine mediated disorder such as an inflammatory disease is provided. 25 The pharmaceutical compositions of the invention are thus useful for the prophylaxis or therapy of inflammatory diseases, in particular chronic or acute inflammation, chronic inflammatory arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, juvenile rheumatoid arthritis, gouty arthritis; psoriasis, erythrodermic psoriasis, 30 pustular psoriasis, inflammatory bowel disease, Crohn's disease and related conditions, ulcerative colitis, colitis, diverticulitis, nephritis, urethritis, salpingitis, oophoritis, endomyometritis, spondylitis, systemic lupus erythematosus and related disorders, multiple sclerosis, asthma, meningitis, myelitis, encephalomyelitis, 30 WO 2011/104340 PCT/EP2011/052813 encephalitis, phlebitis, thrombophlebitis, chronic obstructive disease (COPD), inflammatory lung disease, allergic rhinitis, endocarditis, osteomyelitis, rheumatic fever, rheumatic pericarditis, rheumatic endocarditis, rheumatic myocarditis, rheumatic mitral valve disease, rheumatic aortic valve disease, prostatitis, 5 prostatocystitis, spondoarthropathies ankylosing spondylitis, synovitis, tenosynovotis, myositis, pharyngitis, polymyalgia rheumatica, shoulder tendonitis or bursitis, gout, pseudo gout, vasculitides, inflammatory diseases of the thyroid selected from granulomatous thyroiditis, lymphocytic thyroiditis, invasive fibrous thyroiditis, acute thyroiditis; Hashimoto's thyroiditis, Kawasaki's disease, Raynaud's phenomenon, 10 Sjogren's syndrome, neuroinflammatory disease, sepsis, conjubctivitis, keratitis, iridocyclitis, optic neuritis, otitis, lymphoadenitis, nasopaharingitis, sinusitis, pharyngitis, tonsillitis, laryngitis, epiglottitis, bronchitis, pneumonitis, stomatitis, gingivitis, oesophagitis, gastritis, peritonitis, hepatitis, cholelithiasis, cholecystitis, glomerulonephritis, goodpasture's disease, crescentic glomerulonephritis, 15 pancreatitis, dermatitis, endomyometritis, myometritis, metritis, cervicitis, endocervicitis, exocervicitis, parametritis, tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis, pneumoconiosis, inflammatory polyarthropathies, psoriatric arthropathies, intestinal fibrosis, bronchiectasis and enteropathic arthropathies. 20 As already stated above, the compositions of the present invention are particularly useful for treating or preventing a disease selected from chronic or acute inflammation, chronic inflammatory arthritis, rheumatoid arthritis, psoriasis, COPD, inflammatory bowel disease, septic shock, Crohn's disease, ulcerative colitis, multiple sclerosis and asthma. 25 Thus, in a more preferred embodiment of this invention the use of a thienopyrimidine compound for the production of a pharmaceutical composition for the prophylaxis or therapy of inflammatory diseases selected from chronic or acute inflammation, chronic inflammatory arthritis, rheumatoid arthritis, psoriasis, COPD, inflammatory 30 bowel disease, septic shock Crohn's disease, ulcerative colitis, multiple sclerosis and asthma is provided. 31 WO 2011/104340 PCT/EP2011/052813 In yet a further aspect of the invention the use of a thienopyrimidine compound of the invention for the production of a pharmaceutical composition for treating or preventing cancer, viral diseases or neurodegenerative diseases is provided. 5 For the purpose of the present invention, a therapeutically effective dosage will generally be from about 1 to 2000 mg/day, preferably from about 10 to about 1000 mg/day, and most preferably from about 10 to about 500 mg/day, which may be administered in one or multiple doses. 10 It will be appreciated, however, that specific dose level of the compounds of the invention for any particular patient will depend on a variety of factors such as age, sex, body weight, general health condition, diet, individual response of the patient to be treated time of administration, severity of the disease to be treated, the activity of particular compound applied, dosage form, mode of application and concomitant 15 medication. The therapeutically effective amount for a given situation will readily be determined by routine experimentation and is within the skills and judgment of the ordinary clinician or physician. Abbreviations: 20 CDI: carbonyldiimidazole TEA: triethylamine HATU: (2-(7-aza-1 H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate) TBTU: 2-(1 H-Benzotriazol-1 -yl)-1,1,3,3-tetramethyluroniumtetrafluorborat 25 THF: tetrahydrofuran EE: ethylacetate ACN: acetonitrile EtOH: ethanol MeOH: methanol 30 DCM: methylene chloride DMF: N,N-dimethylformamide EtOAc: ethyl acetate HCI: hydrochloric acid 32 WO 2011/104340 PCT/EP2011/052813 t-BuOH: tert.butanol DTAD: Di-ter-butyl azodicarboxylate DEAD: diethyl azodicarboxylate DIAD: diisopropyl azodicarboxylate 5 LiHMDS: lithium hexymethyldisilazane DIPEA: diisopropylethyl amine EDC: 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimid TFA: trifluoro acetic acid brine: saturated sodium chloride solution in water 10 rt: room temperature min: minute 33 WO 2011/104340 PCT/EP2011/052813 Examples Intermediate I tert- Butyl 2-(2-amino-5-fluorophenoxv)proipvlcarbamate 5 1.1. tert- Butyl 2-(5-fluoro-2-nitrophenoxv)propvlcarbamate >O O <N F 0 0 0 2-Nitro-5-fluorophenol (3.0 g) and tert-butyl-N-(2-hydroxypropyl)carbamate were dissolved in THF (20 ml) and triphenylphosphine (7.5 g) and di-tert-butyl azodicarboxylate were added. The exothermic reaction was cooled in an ice bath. 10 Then the reaction mixture was stirred at room temperature for 2h. The mixture was concentrated in vacuo and the residue was purified by chromatography (silica gel/ dichloromethane: petroleum ether 1:2). The fractions were combined and concentrated in vacuo. The residue was dissolved in dichloromethane and washed with 1 M NaOH. The organic layer was separated, dried, filtered and concentrated in 15 vacuo. Yield: 3.12 g ESI mass spectrum: m/z = 315 (M+H)* 1.2: tert- Butyl 2-(2-amino-5-fluorophenoxv)proipvlcarbamate >O O N F 0 -C 20 N To a solution of tert-butyl 2-(5-fluoro-2-nitrophenoxy)propylcarbamate (3.1 g) in MeOH (5 ml) was added 10% palladium on carbon (300 mg) and the reaction mixture 34 WO 2011/104340 PCT/EP2011/052813 was hydrogenated at room temperature at 50psi. The catalyst was filtered off and the filtrate was concentrated in vacuo. Yield: 2.5 g ESI mass spectrum: m/z = 285 (M+H)* 5 Intermediate 11 Tert-butyl 2-hydroxybutylcarbamate 0 O <N 0 1 -Amino-2-butanol (1.0 g) was dissolved in dichloromethane (50.0 ml) and di-(tert butyl) dicarbonate (2.6 g) was added. The reaction mixture was stirred at room 10 temperature for 4h then washed with 1 M NaOH. The organic layer was separated and concentrated in vacuo. Yield: 1.8 g Intermediate III Methyl 4-(4-fluoro-2-hydroxvphenylamino)-5-methyl 15 th ieno[2,3-dpyrimid ine-6-carboxylate F 0 F_ XO N 0 N N S 0 4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (0.5 g), 2 amino-5-fluorophenol (265.0 mg), p-toluenesulfonic acid monohydrate (75.0 mg) and 20 dioxane (5.0 ml) were combined in a microwave tube. The mixture was heated at 1400C for 15min under microwave irradiation. Then the mixture was allowed to cool to room temperature and a precipitate formed. The precipitate was collected by filtration, washed with dioxane, methanol and Et 2 O to yield the title compound. Yield: 605.0 mg 25 ESI mass spectrum: m/z = 334 (M+H)* 35 WO 2011/104340 PCT/EP2011/052813 Intermediate IV Methyl 4-(2-hydroxvipyridin-3-vlamino)-5-methylthieno[2,3-dpyrimidine-6-carboxylate N kN S O 5 Prepared analogously to example III using 4-chloro-5-methyl-thieno[2,3-d]pyrimidine 6-carboxylic acid methyl ester and 3-amino-2-hydroxypyridine Yield: 258.0 mg ESI mass spectrum: m/z = 317 (M+H)* 10 Intermediate V tert-Butyl 3-(2-amino-5-fluorophenoxv)butylcarbamate V.1 tert- Butyl 2-(5-fluoro-2-nitrophenoxv)proipvlcarbamate ovo F 11 0 N F O 0 15 Prepared analogously to example 1-1 using BOC-4-amino-2-butanol and 2-nitro-5 fluorophenol. Yield: 2.20 g ESI mass spectrum: m/z = 329 (M+H)* 20 V.2 tert-Butyl 3-(2-amino-5-fluorophenoxv)butylcarbamate 36 WO 2011/104340 PCT/EP2011/052813 F 0 -a N Prepared analogously to example 1-2 using tert-butyl 3-(5-fluoro-2 n itrophenoxy)butylcarbamate 5 Yield: 1.8 g Intermediate VI 3-(2-Amino-5-fluoro-phenoxy)-butyric acid ethyl ester 10 Intermediate VI.1 Ethyl 3-(5-fluoro-2-nitrophenoxv)butanoate 0"+0 ON O O F Ethyl 3-Hydroxybutyrate (6.5 ml) was dissolved in THF (350.0 ml) at 00C and NaH (4.8 g) was added. The reaction was stirred at room temperature for 30 min. Then 5,5 g 2,4- difluoronitrobenzene was added and the mixture was heated at reflux 15 overnight. The reaction was concentrated in vacuo and the residue was dissolved in water and dichloromethane. The organic layer was separated, dried and concentrated in vacuo. The residue was purified by chromatography (silica/ dichloromethane) to yield the title compound. Yield: 1.36 g 20 ESI mass spectrum: m/z = 272 (M+H)* VI. 2 3-(2-Amino-5-fluoro-phenoxy)-butyric acid ethyl ester 37 WO 2011/104340 PCT/EP2011/052813 N o -r o0 F To a solution of Ethyl 3-(5-fluoro-2-nitrophenoxylbutanoate (1.3 g) in THF (50 ml) was added Raney nickel (150 mg) and the reaction mixture was hydrogenated. The catalyst was filtered off and the filtrate was concentrated in vacuo. 5 Yield: 2.5 g ESI mass spectrum: m/z = 285 (M+H)* Intermediate VII 3[2-(2-Amino-5-fluoro-phenoxv)-3-tert-butoxvcarbonylamino-propyll-carbamic acid 10 tert-butyl ester VII. 1 (3-tert-Butoxvcarbonylamino-2-hydroxv-proipvl)-carbamic acid tert-butyl ester 0 0 O N N O 0 15 Di-tert-butyl dicarbonate (41.5g) was dissolved in dichloromethane (40.0 ml), a solution of 1,3- diamino-propan-2-ol (8.0g) and triethylamine (1.5 ml) in dichloromethane/methanol (1:5; 100 ml) was added and the reaction mixture was stirred at room temperature overnight. The solution was concentrated in vacuo and the residue was dissolved in dichlormethane. The organic layer was washed with 20 water, separated, dried and concentrated in vacuo. The residue was purfied by chromatography (silica / dichloromethane: methanol 25:1). Yield: 17g ESI mass spectrum: m/z = 291 (M+H)* 25 VII. 2 [3-tert-Butoxvcarbonylamino-2-(5-fluoro-2-nitro-phenox)-propyll carbamic acid tert-butyl ester 38 WO 2011/104340 PCT/EP2011/052813 O O O KN N '0 F 0 - 0 0 2-Nitro-5-fluorophenol (8.4 g) and (3-tert-butoxycarbonylamino-2-hydroxy-propyl) carbamic acid tert-butyl ester (17.0 g) were dissolved in THF (60 ml) and triphenylphosphine (21 g) and di-tert-butyl-azodicarboxylate (18.4 g) were added. 5 The exothermic reaction was cooled in an ice bath. Then the mixture was stirred at room temperature overnight. It was concentrated in vacuo and the residue was dissolved in dichloromethane, washed with water and 1 M NaOH. The organic layer was dried and concentrated in vacuo. The residue was purified by chromatography (silica / dichloromethane:methanol 25:1). 10 Yield: 25 g ESI mass spectrum: m/z = 430 (M+H)* VII.3 3[2-(2-Amino-5-fluoro-phenoxv)-3-tert-butoxvcarbonylamino-propyll-carbamic acid tert-butyl ester O O O 1-N N O F 0 15 N Prepared analogously to example 1-2 using [3-tert-butoxycarbonylamino-2-(5-fluoro 2-nitro-phenoxy)-propyl]-carbamic acid tert-butyl ester Yield: 12.7 g ESI mass spectrum: m/z = 400 (M+H)* 20 Intermediate Vill 4-(2-amino-5-fluorophenoxv)-2-methylpentan-2-ol 39 WO 2011/104340 PCT/EP2011/052813 VIII.1 4-(5-fluoro-2-nitrophenoxv)-2-methylpentan-2-ol 0 F 0 -N 2-Methylpentane-2,4-diol (2.8 ml) was dissolved in THF (20.0 ml) and NaH (60% in mineral oil; 1g) was added. At room temperature 2,4-difluoronitrobenzene was added 5 and the reaction mixture was stirred overnight. Then the reaction was quenched with water and concentrated in vacuo. The residue was dissolved in dichloromethane, washed with water and concentrated in vacuo. Yield: 2.4 g ESI mass spectrum: m/z = 258 (M+H)* 10 VIII. 2 4-(2-amino-5-fluorophenoxv)-2-methylpentan-2-ol F 0 N Prepared analogously to example 1-2 using 4-(5-fluoro-2-nitrophenoxy)-2 methylpentan-2-ol 15 Yield: 2.12 g ESI mass spectrum: m/z = 228 (M+H)* Intermediate IX 2-(1,1,1-Trifluoropropan-2-vloxv)pvridin-3-amine 20 IX. 1 3-Nitro-2-(1,1,1-trifluoropropan-2-vloxv)pvridine F N 01 +..O F N I 0 40 WO 2011/104340 PCT/EP2011/052813 1,1,1- Trifluoro-2-propanol (3.2 g) was dissolved in THF (4.0 ml) and cooled to OC. Then LiHMDS (1 M in THF; 28.3 ml) was added dropwise. The reaction mixture was stirred at 00C for 20 minutes. A solution of 2-fluoro-3-nitro-pyridine (4.0 g) in THF (1 ml) was added and the mixture was stirred overnight. It was quenched by addition 5 of saturated NH 4 CI solution and extracted with dichloromethane. The organic layer was dried and concentrated in vacuo. Yield: 6.24 g ESI mass spectrum: m/z = 237 (M+H)* 10 IX. 2 2-(1,1,1-Trifluoropropan-2-vloxv)pvridin-3-amine F N 0 F UN 3-Nitro-2-(1,1,1-trifluoropropan-2-yloxy)pyridine (6.2 g) was dissolved in methanol (500 ml) and Raney nickel (1.0 g) was added. The reaction mixture was hydrogenated at room temperature and 5 bar. The catalyst was filtered off and the 15 filtrate was concentrated in vacuo. Yield: 4.83 g ESI mass spectrum: m/z = 207 (M+H)* Intermediate X 20 2-(1,3-Difluoropropan-2-vloxy)-4-fluoroaniline X. 1 2-(1,3-Difluoropropan-2-vloxv)-4-fluoro-1 -nitrobenzene F F F 0 I Prepared analogously to example IX.1 using 2,4-difluoronitrobenzene. 25 Yield: 11. 96g X.2 2-(1,3-Difluoropropan-2-vloxv)-4-fluoroaniline 41 WO 2011/104340 PCT/EP2011/052813 F F F N Prepared analogously to example IX. 2 Yield: 4.42 g ESI mass spectrum: m/z = 206 (M+H)* 5 Intermediate XI 2-(2-Fluoropropoxv)pyridin-3-amine XI.1 2-(2-fluoropropoxv)-3-nitroipyridine F N 0 N.. I I 10 0 2-Fluoropropan-1 -ol (93.6 mg) was dissolved in THF (10 ml). LiHMDS in THF(1 M; 1.2 ml) was added and the reaction was stirred for 15 min. Then a solution of 2-fluoro-3 nitro-pyridine (142 mg) in THF was added and the reaction stirred at room temperature overnight. 15 An aqueous solution of K 2

CO

3 (2M; 750 pl) was added to the reaction mixture and filtered over Alox B. The filtrat was concentrated in vacuo. Yield: 200 mg Retention time HPLC: 2.05 min HPLC method: 003_CCZQ6 20 XI.2 2-(2-Fluoropropoxv)pvridin-3-amine F N 0

NH

2 42 WO 2011/104340 PCT/EP2011/052813 2-(2-fluoropropoxy)-3-nitropyridine (199.97 mg) was dissolved in a mixture of THF (10 ml) and methanol (5 ml). Pd/C (20 mg) was added and the mixture was hydrogenated at room temperature for 4h and 3 bar.The mixture was concentrated in vacuo. 5 Yield: 153 mg Retention time HPLC: 1.50 min HPLC method: 002_CCZQ4 Intermediate XII 10 2-(1 -methoxvpropan-2-vloxv)pvridin-3-amine XII.1 2-(1 -methoxvpropan-2-vlox)-3-nitropvridine 0 N 0 y N Prepared analogously to example XI.1 using 2-fluoro-3-nitropyridine (142 mg) and 1 15 methoxypropan-2-ol (108 mg). Yield: 212 mg Retention time HPLC: 2.04 min HPLC method: 003_CCZQ6 20 XII.1 2-(1 -Methoxvpropan-2-vloxv)pvridin-3-amine ox N 0 NH2

NH

2 Prepared analogously to example XI.2 using 2-(1-methoxypropan-2-yloxy)-3 nitropyridine (212 mg). 43 WO 2011/104340 PCT/EP2011/052813 Yield: 165 mg Retention time HPLC: 1.52 min HPLC method: 002_CCZQ4 5 Intermediate XIII 2-(3-Aminopyridin-2vloxv)ethanol XIII.1 2-(3-Nitroipridin-2-vloxv)ethano OH N.. II 10 Ethylene glycole (88.8 mg) was dissolved in THF (10 ml). LiHMDS in THF(1 M; 1.2 ml) was added and the reaction was stirred for 15 min. Then a solution of 2-fluoro-3 nitro-pyridine (142 mg) in THF was added and the reaction was stirred at room temperature overnight. 15 The reaction mixture was concentrated in vacuo and the residue was purified by RP chromatography (H20+ 0,1% TFA/ MeOH= 40%-->99%). Yield: 176 mg Retention time HPLC: 1.68 min HPLC method: 003_CCZQ6 20 XIII.2 2-(3-Aminopvridin-2vloxv)ethanol OH N 0

NH

2 Prepared analogously to example XII.2 using 2-(3-nitropyridin-2-yloxy)ethano (115 25 mg). 44 WO 2011/104340 PCT/EP2011/052813 Yield: 175 mg Retention time HPLC: 1.43 min HPLC method: 003_CCZQ7 5 Intermediate XIV 2-(2,2-Difluoroethoxv)ipridin-3-amine XIV.1 2-(2,2-Difluoroethoxv)-3-nitroipridine F F N 0 N.. II Prepared analogously to example X11.1 using 2-fluoro-3-nitropyridine (142 mg) and 10 2,2-difluoroethanol (98 mg). Yield: 204 mg Retention time HPLC: 1.99 min HPLC method: 003_CCZQ6 15 XIV.2 2-(2,2-Difluoroethoxv)ipridin-3-amine F F N 0

NH

2 Prepared analogously to example XII.2 using 2-(2,2-difluoroethoxy)-3-nitropyridine (204 mg). Yield: 171 mg 20 Retention time HPLC: 1.58 min HPLC method: 002_CCZQ4 Intermediate XV 2-((3-Aminopvridin-2-vloxv)methvl)propane-1,3-diol 25 45 WO 2011/104340 PCT/EP2011/052813 XV. 1 2-((3-Nitropyridin-2-vloxv)methvl)propane-1 ,3-diol OH OH N 0 N.. 11 0 Prepared analogously to example X11.1 using 2-fluoro-3-nitropyridine (142 mg) and 2 (hydroxymethyl)-1,3-propanediol (148 mg) 5 Yield: 130 mg Retention time HPLC: 1.65 min HPLC method: 003_CCZQ6 XV.2 2-((3-Aminopvridin-2-vloxv)methvl)propane-1,3-diol OH OH N 0 10 NH 2 Prepared analogously to example XII.2 using 2-((3-nitropyridin-2 yloxy)methyl)propane-1,3-diol (130 mg). Yield: 99 mg 15 Intermediate XVI 2-(1-((3-Aminopvridin-2-vloxv)methvl)cyclopropvl)acetonitrile XVI. 1 2-(1 -((3-Nitropvridin-2-vloxv)methvl)cyclopropvl)acetonitrile N 0 N - +O N 11 0 46 WO 2011/104340 PCT/EP2011/052813 Prepared analogously to example XI.1 using [1-(hydroxymethyl)cyclopropyl] acetonitrile (267 mg) Yield: 488 mg Retention time HPLC: 1.82 min 5 HPLC method: 004_CCZQ6 XVI.2 2-(1-((3-Aminopvridin-2-vloxv)methvl)cyclopropvl)acetonitrile N 0 N 2-(1-((3-Nitropyridin-2-yloxy)methyl)cyclopropyl)acetonitrile (466 mg) was dissolved 10 in a mixture of glacial acetic acid (4 ml) and ethanol (8 ml). Ferrum (1.1 g) was added and the reaction mixture was heated to100 C for 2h. The mixture was concentrated in vacuo and the residue was dissolved in dichloromethane, extracted with an aqueous solution of K 2

CO

3 (2M) and concentrated in vacuo Yield: 264 mg 15 Retention time HPLC: 2.07 min HPLC method: 003_CCZQ7 Intermediate XVII 2-((2,2-Difluorocyclopropvl)methoxv)ipridine-3-amine 20 XVII.1 2-((2,2-Difluorocyclopropvl)methoxv)-3-nitropvridine FEF N 0 N 11 Prepared analogously to example XII.1 using (2,2-difluorocyclopropyl)methano and 2-fluoro-3-nitro-pyridine 25 Yield: 469 mg Retention time HPLC: 2.00 min 47 WO 2011/104340 PCT/EP2011/052813 HPLC method: 004_CCZQ6 XVII.2 2-((2,2-Difluorocyclopropyl)methoxv)ipridine-3-amine F F N 0

NH

2 5 Prepared analogously to example XII.2 using 2-((2,2-difluorocyclopropyl)methoxy)-3 nitropyridine Yield: 391 mg Retention time HPLC: 1.45 min HPLC method: 004_CCZQ6 10 Intermediate XVIII 4-[2-( -Ethylcabamoyl-ethoxy)-4-fluoro-phenylaminol-5-methyl-thieno [2,3d1 pyrimidine-6-carboxylic acid methyl ester N 0 FO F 0 N 0 N I kN S /0 15 XVIII.1 4-(4-fluoro-2-methoxy-phenylamino)-5-methyl-thieno[2,3-dlpyrimidine-6 carboxylic acid methyl ester F 0 N 0 N I kN S 0 4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (15.0 g), 4 fluoro-2-methoxyaniline (9.5 g), 4M hydrochloric acid in dioxane (4.5 ml) and 48 WO 2011/104340 PCT/EP2011/052813 dioxane (100.0 ml) were stirred at 100 C overnight. Then the mixture was filtrated and the solid was dried in vacuo. Yield: 24.0 g ESI mass spectrum: m/z = 348 (M+H)* 5 XVIII.2 4-(4-Fluoro-2-hydroxy-phenylamino)-5-methyl-thieno[2,3-dlpyrimidine-6 carboxylic acid methyl ester F 0 N 0 N I kN S /0 The resulting product from XVIII.1 (24.0 g) was dissolved in DCM (500 ml) and was 10 cooled with a dry ice bath.To the mixture was dropped slowly boron tribromide (35 ml) and stirred for 30 min. The mixture was allowed to cool to room temperature overnight. Then the mixture was cooled with an dry ice bath, dropped 100 ml methanol to the mixture, stirred for 30 min and concentrated. The residue was suspended in methonol and stirred at reflux for 1 hour. 15 The mixture was filtrated and dried in vacuo. Yield: 18.6 g ESI mass spectrum: m/z = 334 (M+H)* Retention time HPLC: 2.16 min HPLC method: 007_CCZQ5 20 XVIII.3 4-[2-(1 -tert-Butoxvcyrbonyl-ethoxy)-4-fluoro-phenylaminol-5-methyl thieno[2,3-dlpyrimidine-6-carboxylic acid methyl ester 0 1 051 F 0 N 0 N I N S 0 49 WO 2011/104340 PCT/EP2011/052813 To the resulting product from XVIII.2 (2.0 g) was added 2-bromopropionic acid tert butyl ester (1.4 g), cesium carbonate (4.8 g) and ACN (50 ml). The mixture was stirred at 600C for 2 hours. Then water was added and the mixture was filtrated. Yield: 2.1 g 5 ESI mass spectrum: m/z = 462 (M+H)* XVIII .4 4-[2-(1 -Carboxy-ethoxy)-4-fluoro-phenylaminol-5-methyl thieno[2,3-dlpyrimidine-6-carboxylic acid methyl ester 0 0 1 F 0 N 0 N I kN S /0 10 To the resulting product from XVIII.3 (2.1 g) was added trifluoroacetic acid 50% in DCM (20 ml) and stirred at rt overnight. The mixture was concentrated and triturated with diethylether. Yield: 1.9 g ESI mass spectrum: m/z = 406 (M+H)* 15 Retention time HPLC: 1.96 min HPLC method: Method A_9 XVIII.5 4-[2-(1 -Ethylcarbamoyl-ethoxy)-4-fluoro-phenylaminol-5-methyl thieno[2,3-dlpyrimidine-6-carboxylic acid methyl ester 0-5 N 0 N 20 To the resulting product from XVIII.4 (0.5 g) in ACN (10 ml) was added TBTU (0.4 g) and TEA (0.43 ml). The mixture was stirred at rt for 20 min. To the mixture was 50 WO 2011/104340 PCT/EP2011/052813 added ethylamine (2 mol/I (1.5 ml)) and stirred at rt overnight. Then the mixture was concentrated and triturated with diethylether. The mixture was diluted with methanol and purified by chromatography. Yield: 0.36 g 5 ESI mass spectrum: m/z = 433 (M+H)* Retention time HPLC: 1.89 min HPLC method: Method A_9 Intermediate XIX 10 4-Amino-3-(2-fluoro-1 -fluoromethyl-ethoxv)-benzonitrile F F 0 N XIX. 1 3-(2-Fluoro-1 -fluoromethyl-ethoxy)-4-nitro-benzonitrile F F ao0 N 1,3-Difluoro-propan-2-ol (4.2 g) was dissolved under argon in THF (250 ml) and 15 cooled to OC. LiHMDS (28 ml) was added to the mixture and stirred at rt for 1 hour. Then the mixture was cooled to OC and 3-fluoro-4-nitrobenzonitrile (1.95 ml) was added in portions and stirred for 2 hours. The mixture was poured in water and extracted with DCM. The organic layer was washed with water, dried and concentrated. 20 Yield: 4.9 g XIX.2 4-Amino-3-(2-fluoro-1 -fluoromethyl-ethoxv)-benzonitrile F F 0 N 51 WO 2011/104340 PCT/EP2011/052813 3-(2-Fluoro-1-fluoromethyl-ethoxy)-4-nitro-benzonitrile (1.45 g), tin(II) chloride dihydrate (4.00 g) and ethanol (60 ml) were stirred at 100 C for 2 hours. The mixture was poured in water and extracted with DCM. The organic layer was washed with water, dried and concentrated. 5 Yield: 1.04 g Intermediate XXIV 4-Chloro-5-methyl-thieno[2,3-dlpyrimidine-6-carboxylic acid amide CI N N 10 XXIV.1 5-Amino-4-cyano-3-methyl-thiophene-2-carboxylic acid methyl ester N N S 0 To a mixture of methylacetoacetate (80.9 ml), malononitrile (49.5 g), sulfur (24 g) in methanol (750 ml) was added morpholin (139.4 ml). The mixture was stirred at rt for 10 min. Then the mixture was stirred at reflux for 3.5 hours. After that time the 15 mixture was cooled with an ice bath and filtrated.The solid was washed with methanol and oven dried at 600C. Yield: 88.2 g ESI mass spectrum: m/z = 197 (M+H)* 20 XXIV.2 5-Methyl-4-oxo-3,4-dihydro-thieno[2,3-dpyrimidine-6-carboxylic acid methyl ester 0 N 0 N S O To the product from XXIV.1 (70 g) was added formic acid (875 ml) and the mixture was stirred at reflux overnight. The mixture was cooled down, poured in ice water 25 and filtrated. The solid was washed with water and a small portion of methanol. Then the residue was triturated with diethylether. Yield: 72.98 g ESI mass spectrum: m/z = 225 (M+H)* 52 WO 2011/104340 PCT/EP2011/052813 XXIV.3 5-Methyl-4-oxo-3,4-dihydro-thieno[2,3-dpyrimidine-6-carboxylic acid 0 N S 0 The product from XXIV.2 (1 g), sodium hydroxide 4M (5 ml) and methanol were 5 stirred at reflux for 1 hour. At rt 5 ml hydrochloric acid 4M were added and the mixture was filtrated. The solid was washed with water and dried at 600C in an oven overnight. Yield: 950 mg ESI mass spectrum: m/z = 211 (M+H)* 10 XXIV.4 4-Chloro-5-methyl-thieno[2,3-dlpvrimidine-6-carbonyl chloride CI N 0 N -5 CI DMF (0.2 ml) was added to a mixture of the product from XXIV.3 (1 g) and thionylchloride (10 ml). The mixture was stirred at reflux for 1 hour. Then the mixture 15 was concentrated. Yield: 1.2 g XXIV.5 4-Chloro-5-methyl-thieno[2,3-dlpvrimidine-6-carboxylic acid amide CI N 0 20 N N The product from XXIV.4 (1 g) was dissolved warm in ACN (10 ml). This mixture was added dropwise to an ice cooled solution of concentrated ammonia (20 ml) and stirred for 15 min. The mixture was filtrated. The solid was washed with water and oven dried at 500C. 25 Yield: 677 mg ESI mass spectrum: m/z = 226 (M+H)* Retention time HPLC: 0.766 min 53 WO 2011/104340 PCT/EP2011/052813 HPLC method: M2-SB-C18 Intermediate XXVI 3-(2-Amino-5-fluoro-phenoxv)-2-methyl-butan-2-o F 0 5 N XXVI.1 2-Methyl-butane-2,3-diol O 0 3-Hydroxy-3-methyl-2-butanon (5 ml) was dissolved in ethanol (20 ml). PtO2 (100 mg) was added and the mixture was hydrogenated at room temperature for 4h and 3 10 bar.The mixture was concentrated in vacuo. Yield: 3.87 g XXVI.2 3-(5-Fluoro-2-nitro-phenoxv)-2-methyl-butan-2-ol F 0 N 0 15 Prepared analogously to example XX.2 using the product from XXVI.1 (0.9 ml). Yield: 1.7 g ESI mass spectrum: m/z = 261 (M+H)* Retention time HPLC: 1.185 min HPLC method: M2-SB-C18 20 XXVI.3 3-(2-Amino-5-fluoro-phenoxv)-2-methyl-butan-2-o F 0 N Prepared analogously to example XI.2 using the product from XXVI.2 (1.7 g). 54 WO 2011/104340 PCT/EP2011/052813 Yield: 1.45 g ESI mass spectrum: m/z = 214 (M+H)* Retention time HPLC: 0.681 min HPLC method: M2-SB-C18 5 Compound 1 tert-Butyl 2-(5-fluoro-2-(5-methyl-6-(methvlcarbamovl)thieno[2,3-dlpyrimidin-4 ylamino)phenoxv)propylcarbamate 10 1.1 Methyl 4-(2-(1-tert-butoxvcarbonylamino)propan-2-vloxy)-4 fluorophenylam ino)-5-methyl-th ieno[2,3-dpyrim id ine-6-carboxylate >O O N F 0 N 0 N I kN S /0 4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (2.0 g), tert butyl 2-(2-amino-5-fluorophenoxy)propylcarbamate (2.3 g) and Honig's base (4.2 ml) 15 were dissolved in dioxane (70 ml). The reaction mixture was heated at 100 C for three days. Then the reaction was cooled and the precipitate was filtered, washed with dioxane, water and diethylether. Yield: 1.4 g ESI mass spectrum: m/z = 491 (M+H)* 20 Retention time HPLC: 3.36 min HPLC method: A_4 1.2 4-(2-(1 -(tert-Butoxvcarbonylamino)propan-2-vloxy)-4-fluorophenylamino)-5 methyl-thieno[2,3-dlpyrimidine-6-carboxylic acid 55 WO 2011/104340 PCT/EP2011/052813 O N F 0 N 0 N I kN S 0 Methyl 4-(2-(1-tert-butoxycarbonylamino)propan-2-yloxy)-4-fluorophenylamino)-5 methylthieno[2,3-d]pyrimidine-6-carboxylate (700 mg) and NaOH (1 M; 3.6 ml) was dissolved in a mixture of methanol and THF (1:1; 20 ml). The reaction was stirred at 5 room temperature overnight. Aqueous HCI (1 M; 3.6 ml) was added and the organic solvent was evaporated. The residue was triturated with water and filtered. The residue was washed with water, methanol and Et 2 O and dried at 600C. Yield: 0.63 g ESI mass spectrum: m/z = 477 (M+H)* 10 Retention time HPLC: 1.96 min HPLC method: A_9 1.3 tert-Butyl 2-(5-fluoro-2-(5-methyl-6-(methvcarbamovl)thieno[2,3-dlpvrimidin-4 Vlamino)phenoxv)propyvlcarbamate O 0 N F 0 N N-

N

15 N S 0 To a solution of 4-(2-(1-(tert-Butoxycarbonylamino)propan-2-yloxy)-4 fluorophenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid (80 mg) in DMF (1 ml), TBTU (54 mg) and triethylamine (60 pl) were added.The mixture was stirred at room temperature for 5 min then methylamine in THF (2M; 420 pl) was 20 added and the reaction stirred at room temperature overnight. The mixture was 56 WO 2011/104340 PCT/EP2011/052813 diluted with methanol and purified directly by RP-chromatography (water with 0.2% trifluoroacetic acid/ methanol 72-100%) to give the title compound. Yield: 38 mg ESI mass spectrum: m/z = 490 (M+H)* 5 Retention time HPLC: 1.86 min HPLC method: A_9 Further analogues of 1: The compounds listed in table 1 were synthesized analogously to example 1.3 using 10 4-(2-(1 -(tert-butoxycarbonylamino)propan-2-yloxy)-4-fluorophenylamino)-5 methylthieno[2,3-d]pyrimidine-6-carboxylic acid and the corresponding amine. Table 1: Reten HPLC Structure Name Yield Mass tion method time 1 Otert-Butyl 2-(2-(6-(3 O N (dimethymino)propyl carbamoyl) F O 5-methyl-thieno[2,3- 35 d]pyrimidin-4- 561 1.41 A_9 N N ylamino)-5- mg N fluorophenoxy)propyl N S O carbamate 1.5 tert-Butyl 2-(5-fluoro-2 o N (6-(2-hydroxyethyl carbamoyl)-5- 35 F methylthieno[2,3 d]pyrimidin-4-yl- mg - N N amino)phenoxy)propyl carbamate N S 0 15 Compound 2 57 WO 2011/104340 PCT/EP2011/052813 2.1 Methyl 4-(2-(1-aminopropan-2-vloxy)-4-fluorophenylamino)-5-methyl th ieno[2,3-dlipyri mid i ne-6-carboxyl ate trifluoroacetate 0 F N 0 y y F F 0 N N 0 kN S /0 Methyl 4-(2-(1-tert-butoxycarbonylamino)propan-2-yloxy)-4-fluorophenylamino)-5 5 methyl-thieno[2,3-d]pyrimidine-6-carboxylate (500 mg) was dissolved in a solution of 25% trifluoracetic acid in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 2h and then concentrated in vacuo. Yield: 460 mg ESI mass spectrum: m/z = 391 (M+H)* 10 Retention time HPLC: 1.31 min HPLC method: A_9 Further analogues of 2: The compounds listed in table 2 were synthesized analogously to example 2.1 using 15 the corresponding BOC protected derivatives shown in Table 1. Table 2: Reten HPLC Structure Name Yield Mass tion method time 2.2 0 F 0 0 F F 4-(2-(1-Amino-propan F N 0 F 2-yloxy)-4 F fluorophenylamino)-N F O (3-(diemthyl- 35 N N- amino)propyl)-5- mg 461 1.03 A_9 N N methylthieno[2,3-9 N N d]pyrimidine-6 carboxamide N S 0 bis(trifloroacetate) 58 WO 2011/104340 PCT/EP2011/052813 2.3 N 4-(2-(1-Amino-propan 2-yloxy)-4 F 0 fluorophenylamino)-N- 13 (2-hydroxy-ethyl)-5- 420 1.16 A_9 N o methyl-thieno[2,3-d]- mg N N pyrimidine-6 carboxamide N S 0 2.4 0 F N 0 F 4-(2-(1-Amino-propan F 2-yloxy)-4 fluorophenylamino)-N- 24 F O 5-methyl-thieno[2,3-d]- 390 1.16 A_9 pyrimidine-6- mg N carboxamide N N trifluoroacetate N S 0 Compound 3 Methyl 4-(4-fluoro-2-(1-(methylsulfonamido)propan-2-vloxv)phenylamino)-5-methyl th ieno[2,3-dpyrimid ine-6-carboxylate 5 3.1 Methyl 4-(4-fluoro-(2-(1-methylsulfonamido)propan-2-vloxv)phenylamino)-5 methyl -th ieno[2,3-dlipyrim id ine-6-carboxyl ate 00 N ~ F O N s 0 N S 0 10 To a solution of Methyl 4-(2-(1-aminopropan-2-yloxy)-4-fluorophenylamino)-5 methyl-thieno[2,3-d]pyrimidine 6-carboxylate trifluoroacetate (80 mg) and triethylamine (55 pl) in dichloromethane (1.5 ml), methansulfonyl chloride (16 pl) was added. The reaction mixture was stirred at room temperature overnight. Then the 15 reaction was quenched with water and methanol. The organic layer was separated and concentrated in vacuo. 59 WO 2011/104340 PCT/EP2011/052813 Yield: 68 mg ESI mass spectrum: m/z = 469 (M+H)* Retention time HPLC: 1.99 min HPLC method: A_9 5 Further analogues of compound 3 The compounds listed in table 3 were synthesized analogously to example 3.1 using the appropriate amine and the corresponding chloride. 10 Table 3: 60 WO 2011/104340 PCT/EP2011/052813 Reten HPLC Chlo Structure Name Yield Mass tion method ride time 3.2 N0 Methyl 4-(4-fluoro-2 (1-(1 F methylethylsulfon- 28 amido)propan-2yloxy)- 497 1.99 A_9 N phenylamino)-5- mg methyl-thieno[2,3 N 0 d]pyrimidine-6 N S O__ carboxylate 3.3 N-(3 O (Dim eth ylam ino)propyl 7 )-4-(4-fluoro-2-(1-0 T methyl- 5.1 F 0 sulfonamido)propan-2- 539 1.28 A_9 o N N- yloxy)phenylamino)-5- mg NC N methylthieno[2,3 N d]pyrimidine-6-carbox N S O amide 3.4 N J0 Methyl 4-(2-(1-acet amidopropan-2-yloxy)- AAL o F 0 4-fluorophenylamino)- 64 5-methylthieno[2,3- 433 1.82 CMS2 ci N d]pyrimidine-6- mg N carboxylate N S o 3.5 N 0 Methyl 4-(4-fluoro2-(1 isobutyramidopropan- A AL o F 02-yloxy)phenylamino)- 58 5-methylthieno[2,3-d]- 461 1.99 CMS2 ci N pyrimidine-6- 9 carboxylate N 0 N N S 0 Compound 4 Methyl 4-(2-(1-dimethylamino)propan-2vloxy)-4-fluorophenylamino)-5-methyl th ieno[2,3-dlipyri mid i ne-6-carboxyl ate trifluoroacetate 5 61 WO 2011/104340 PCT/EP2011/052813 N 0 F O F F 0 F N kN S O Methyl 4-(2-(1-aminopropan-2-yloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3 d]pyrimidine-6-carboxylate trifluoroacetate (100 mg) was dissolved in THF (2.5 ml), 5 NaOH (4M; 55 pl) and formaldehyde 37% in water (55 pl) was added. The reaction mixture was stirred a few minutes. Then sodium triacetoxyborohydride (220 mg) was added.and the reaction was stirred at room temperature for 4h. Then the mixture was concentrated in vacuo. The residue was dissolved in dichloromethane and washed with aqueous NaOH (1 M). The organic layer was separated and concentrated in 10 vacuo. The product was purified by RP-chromatography (water with 0.2% trifluoroacetic acid/ methanol 72-100%) to afford the title compound. Yield: 83mg ESI mass spectrum: m/z = 419 (M+H)* Retention time HPLC: 1.32 min 15 HPLC method: A_9 Compound 5 tert-Butyl 2-(2-(6-carbamovl-5-methyl-thieno[2,3-dlpvrimidin-4-vlamino)-5 fluorophenoxv) propvlcarbamate 0 <N F 0 N F O 20 N S 0 62 WO 2011/104340 PCT/EP2011/052813 4-(2-(1 -(tert-Butoxycarbonylamino)propan-2-yloxy)-4-fluorophenylamino)-5-methyl thieno[2,3-d]pyrimidine-6-carboxylic acid (250mg) and TBTU (170 mg) was dissolved in DMF (3 ml) and triethylamine (190 pl) was added. The mixture was stirred at room temperature for 10 min, then 0.5 ml conc. ammonia was added. The reaction was 5 stirred for 2h. Then the reaction mixture was concentrated in vacuo and purified by RP-chromatography (water with 0.2% trifluoroacetic acid/ methanol 72-100%) to give the title compound. Yield: 55 mg ESI mass spectrum: m/z = 476 (M+H)* 10 Retention time HPLC: 1.80 min HPLC method: A_9 Compound 6 ( R) and (S)-4-(2-(1-aminopropan-2-vloxv)-4-fluorophenvlamino)-5-methyl-thieno[2,3 15 dvpyrimidine-6-carboxamide trifluoroacetate 6.1 (R) and (S)- tert-butyl 2-(2-(6-carbamovl-5-methyl-thieno[2,3-dlpyrimidin-4 Vlam ino)-5-fl uorophenoxv)proipvlcarbamate Chiral O N F 0 N kN S 0 20 The racemate of example 5 was separated by means of HPLC to afford the two enantiomers. The configuration was assigned arbitrarily. Enantiomer A: Yield: 10 mg 25 ESI mass spectrum: m/z = 476 (M+H)* Retention time HPLC: 1.80 min 63 WO 2011/104340 PCT/EP2011/052813 HPLC method: A_9 Enantiomer B: Yield: 14.2 mg 5 ESI mass spectrum: m/z = 476 (M+H)* Retention time HPLC: 1.80 min HPLC method: A_9 6.2 (R) and (S)-4-(2-(1-aminopropan-2-vloxv)-4-fluorophenvlamino)-5 10 methylthieno[2,3-dlpvrimidine-6-carboxamide trifluoroacetate 0 Chiral F F

NH

2 F 0 N N- NH 2 kN S 0 Prepared analogously to example 2.1 from (S)- tert-butyl 2-(2-(6-carbamoyl-5 methylthieno[2,3-d]pyrimidin-4-ylamino)-5-fluorophenoxy)propylcarbamate and the 15 enantiomer, respectively. The configuration was assigned arbitrarily. Enatiomer A Yield: 7 mg ESI mass spectrum: m/z = 376 (M+H)* 20 Retention time HPLC: 1.16 min HPLC method: A_9 Enantiomer B Yield: 11 mg 25 ESI mass spectrum: m/z = 376 (M+H)* Retention time HPLC: 1.16 min 64 WO 2011/104340 PCT/EP2011/052813 HPLC method: A_9 Compound 7 4-(2-(1 -Aminopropan-2-vloxv)-4-fluorophenvlamino)-5-methyl-thieno[2,3 5 dl pyrimidine-6-carboxylic acid trifluoroacetate 0 F HO F

NH

2 F 0 N N 0 N S OH Synthesized analogously to example 2-1 from 4-(2-(1 -(tert-butoxycarbonyl amino)propan-2-yloxy)-4-fl uorophenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6 carboxylic acid 10 Yield: 89 mg ESI mass spectrum: m/z = 377 (M+H)* Retention time HPLC: 1.26 min HPLC method: A_9 15 Compound 8 4-(4-Fluoro-2-(1-(3,3,3-trifluoropropylamino)propan-2-vloxv)phenvlamino-5-methyl th ieno[2,3-dvpyrimid ine-6-carboxamide 8.1 4-(2-(1 -Aminopropan-2-vloxv)-4-fluorophenvlamino)-5-methyl-thieno[2,3 20 dvpyrimidine-6-carboxamide trifluoroacetate 65 WO 2011/104340 PCT/EP2011/052813 0 F F N F 0 N kN S 0 tert-Butyl 2-(2-(6-carbamoyl-5-methylthieno[2,3-d]pyrimidin-4-ylamino)-5 fluorophenoxy)propylcarbamate (740mg) was dissolved in dichloromethane (20 ml) and trifluoroacetic acid (4 ml) was added and the reaction was stirred at room 5 temperature overnight. The reaction was concentrated in vacuo to give the title compound. Yield: 667 mg ESI mass spectrum: m/z = 376 (M+H)* 10 8.2 4-(4-Fluoro-2-(1-(3,3,3-trifluoropropylamino)propan-2-vloxv)phenvlamino-5 methyl-thieno[2,3-dlpvrimidine-6-carboxamide F F N F 0 N N N 4-(2-(1 -Aminopropan-2-yloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3 d]pyrimidine-6-carboxamide 2,2,2-trifluoroacetate (200 mg) was dissolved in THF (20 15 ml) and buffer pH 5 (2 ml), 3,3,3,-trifluoropropanal (50.4 mg) and sodium cyanoborohydride (30.8 mg) were added. The reacion was stirred at room temperature for 4 days.The residue was diluted with 10 ml water, then the organic solvent was evaporated. The residual aqueous fraction 66 WO 2011/104340 PCT/EP2011/052813 was extracted with ethylacetate. The organic layer was separated, dried and concentrated in vacuo. Yield: 190 mg ESI mass spectrum: m/z = 472 (M+H)* 5 Retention time HPLC: 1.38 min HPLC method: A_10 Compound 9 Methyl 4-(2-(2-aminoethoxy)-4-fluorophenylamino)-5-methyl-thieno[2,3-dlpyrimidine 10 6-carboxylate hydrochloride 9.1 Methyl 4-(2-(2-(tert-butoxvcarbonylamino)ethoxy)-4-fluorophenylamino)-5 methyl -th ieno[2,3-dlipyrim id ine-6-carboxyl ate O O NH F NH NH N 1 0 N S 0 15 Methyl 4-(4-fluoro-2-hydroxyphenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6 carboxylate (80.0 mg), Boc-amino-ethanol (50.0 mg) and polymer-bound triphenylphosphine (240.0 mg) was suspended in THF (3.0 ml). The mixture was stirred at room temperature for 5 min. Then di-tert-butyl azodicarboxylate (165.0 mg) was added and the mixture stirred at room temperature overnight. To this reaction 20 celite was added, the resulting mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by RP-chromatography (water with 0.2% trifluoroacetic acid/ methanol 59-100%) Yield: 25.0 mg ESI mass spectrum: m/z = 477 (M+H)* 25 Retention time HPLC: 2.12 min HPLC method: A_9 67 WO 2011/104340 PCT/EP2011/052813 9.2 Methyl 4-(2-(2-aminoethoxy)-4-fluorophenylamino)-5-methyl thieno[2,3-dpyrimidine-6-carboxylate hydrochloride CI N F 0 N N 0 Ko 5 kN S 0 Methyl 4-(2-(2-(tert-butoxycarbonylamino)ethoxy)4-fluorophenylamino)-5-methyl thieno[2,3-d]pyrimidine-6-carboxylate (20 mg) was dissolved in 25% solution of trifluoroacetic acid in dichlormethane (2 ml). The reaction was stirred at room 10 temperature for 2h. The solvent was concentrated in vacuo and the residue was dissolved in methanol and triturated with HCI in methanol. Yield: 15 mg ESI mass spectrum: m/z = 377 (M+H)* Retention time HPLC: 1.28 min 15 HPLC method: A_9 Compound 10 Methyl 4-(2-(1-aminobutan-2vloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3 dlpyrimidine-6-carboxylate hydrochloride 20 10.1 Methyl 4-(2-(1-(tert-butoxycarbonylamino)butan-2-yloxy)-4 fluorophenylam ino)-5-methyl-th ieno[2,3-dpyrimid ine-6-carboxylate 68 WO 2011/104340 PCT/EP2011/052813 0 O <N F 0 N N 1 0 N S 0 Synthesized analogously to example 9.1 using methyl 4-(4-fluoro-2 hydroxyphenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate and tert-butyl 2 hyd roxybutyl carbamate. 5 Yield: 36 mg ESI mass spectrum: m/z = 505 (M+H)* Retention time HPLC: 2.24 min HPLC method: A_9 10 10.2 Methyl 4-(2-(1-aminobutan-2yloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3 d]pyrimidine-6-carboxylate hydrochloride CI N F 0 N N 0 N S 0 Synthesized analogously to example 9.2 using methyl 4-(2-(1-(tert butoxycarbonylamino)butan-2-yloxy)-4-fluorophenylamino)-5-methylthieno[2,3 15 d]pyrimidine-6-carboxylate Yield: 21 mg ESI mass spectrum: m/z = 405 (M+H)* Retention time HPLC: 1.38 min HPLC method: A_9 20 69 WO 2011/104340 PCT/EP2011/052813 Compound 11 Methyl 4-(2-(1-aminopropan-2vloxy)-pyridin-3-vlamino)-5-methyl-thieno[2,3 dlpyrimidine-6-carboxylate hydrochloride 5 11.1 Methyl 4-(2-(1 -(tert-butoxvcarbonylamino)propan-2-vloxv)pyridin-3-vlamino)-5 methyl -th ieno[2,3-dlipyrim id ine-6-carboxyl ate O O <N N 0 N 0 N S 0 Prepared analogously to example 9.1 using methyl 4-(2-hydroxypyridin-3-ylamino)-5 methylthieno[2,3-d]pyrimidine-6-carboxylate and tert-butyl N-(2-hydroxypropyl) 10 carbamate. Yield: 65 mg ESI mass spectrum: m/z = 474 (M+H)* Retention time HPLC: 1.97 min HPLC method: A_9 15 11.2 Methyl 4-(2-(1-aminopropan-2vloxy)-pyridin-3-vlamino)-5-methyl-thieno[2,3 dlpyrimidine-6-carboxylate hydrochloride CI N yO N 0 N N 0 kN S 0 Prepared analogously to example 9.2 using methyl 4-(2-(1 -(tert-butoxycarbonyl 20 amino)-propan-2-yloxy)pyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6 carboxylate 70 WO 2011/104340 PCT/EP2011/052813 Yield: 14 mg ESI mass spectrum: m/z = 374 (M+H)* Retention time HPLC: 1.29 min HPLC method: A_9 5 Compound 12 Methyl 4-(2-(4-aminobutan-2vloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3 dlpyrimidine-6-carboxylate hydrochloride CI N F 0 N S 0 10 4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (1.25 g), tert-butyl 3-(2-amino-5-fluorophenoxy)butylcarbamate (1.7 g) and p-toloulsulfonic acid (175 mg) was dissolved in dioxane (30ml) and the solution was heated under reflux overnight. Then the reaction mixture was concentrated in vacuo. The residue was treated with trifluoracetic acid 25% in dichloromethane and stirred at room 15 temperature for 1 h. The solution was concentrated in vacuo and the residue was dissolved in dichloromethane and washed with sodium bicarbonate. The organic phase was separated, dried and concentrated in vacuo. The residue was triturated with Et 2 O and the precipitate was filtered. Yield: 2.14 g 20 ESI mass spectrum: m/z = 405 (M+H)* Retention time HPLC: 1.36 min HPLC method: A_9 Compound 13 25 Methyl 4-(4-fluoro-2-(4-(methylsulfonamido)butan-2vloxv)phenylamino)-5-methyl th ieno[2,3-dpyrim id ine-6-carboxylate 71 WO 2011/104340 PCT/EP2011/052813 0"N F 0 N s 0 kN S 0 Methyl 4-(2-(4-aminobutan-2yloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3 d]pyrimidine-6-carboxylate hydrochloride (80 mg) and triethylamine (65 pl) were dissolved in dichloromethane (1.5 ml) and methansulfonyl chloride (18 pl) was 5 added. The reaction mixture was stirred at room temperature overnight. Then the mixture was diluted with water and some methanol. The organic layer was separated and concentrated in vacuo. The residue was purified by RP-chromatography (water with 0.2% trifluoroacetic acid/ methanol 59-100%) Yield: 33 mg 10 ESI mass spectrum: m/z = 483 (M+H)* Retention time HPLC: 1.94 min HPLC method: A_9 Further analogues of compound 13 15 The compounds listed in table 4 were synthesized analogously to example 13 using the appropriate amine and the corresponding chlorides or isocyanate. Reten HPLC Chloride/ Structure Name Yield Mass tion tie method Isocyanats time 13.2 0 N Methyl 4-(2-(4 acetamidobutan -2-yloxy)-4- 11 0 F O fluorophenylami 447 1.86 A_9 no)-5-methyl- mg CI N thieno[2,3 N0O d]pyrimidine-6 N S0- carboxylate 72 WO 2011/104340 PCT/EP2011/052813 13.3 N Methyl 4-(4 fluoro-2-(4 isobutyramidob 26 F O utan-2-yloxy)- 475 2.0 A_9 phenylamino)-5- mg N methylthieno[2, 3-d]pyrimidine N 6-carboxylate N S 0 13.4 N 0 Methyl 4-(2-(4 N (3-butylureido) butan-2-yloxy)- 57 4-fluorophenyl- 504 2.05 A_9 F O amino)-5- mg N methylthieno[2, I N 3-d]pyrimidine- 0 NO 6-carboxylate N S 0 Compound 14 Methyl 4-(2-(dimethylamino)butan-2vloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3 dl pyrimidine-6-carboxylate trifluoroacetate 1 0 N 0 F YF F F 0 N 5 k N : Prepared analogously to example 4.1 using methyl 4-(2-(4-aminobutan-2yloxy)-4 fluorophenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate hydrochloride Yield: 53 mg ESI mass spectrum: m/z = 433 (M+H)* 10 Retention time HPLC: 1.38 min HPLC method: A_9 Compound 15 73 WO 2011/104340 PCT/EP2011/052813 Methyl 4-(2-((4-aminobutan-2vloxv)pyridin-3vlamino)-5-methyl-thieno[2,3 dl pyrimidine-6-carboxylate trifluoracetate 15.1 Methyl 4-(2-((4-aminobutan-2vloxv)ipridin-3vlamino)-5-methylthieno[2,3 5 dlpyrimidine-6-carboxylate N 0 N N N S 0 Prepared analogously to example 1.1 using 4-Chloro-5-methyl-thieno[2,3 d]pyrimidine-6-carboxylic acid methyl ester and tert-butyl 3-(3-aminopyridin 2yloxy)butyl carbamate 10 Yield: 1 g ESI mass spectrum: m/z = 488 (M+H)* 15.2 Methyl 4-(2-((4-aminobutan-2vloxv)pyridin-3vlamino)-5-methyl-thieno[2,3 dl pyrimidine-6-carboxylate trifluoroacetate N 0 N 0 FF F N 15 N \ : Prepared analogously to example 1.2 from methyl 4-(2-((4aminobutan-2yloxy)pyridin 3ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate trifluoroacetate Yield: 100 mg ESI mass spectrum: m/z = 388 (M+H)* 20 Retention time HPLC: 1.26 min HPLC method: A_10 74 WO 2011/104340 PCT/EP2011/052813 Compound 16 4-(2-(4-Aminobutan-2-vloxv)pvridin-3-vlamino)-N-(3-(dimethylamino)propl )-5 methylthieno[2,3-dlpvrimidine-6-carboxamide bis-trifluoroacetate 5 16.1 4-(2-(4-(tert-Butoxvcarbonylamino)butan-2vloxv)pyridin-3vlamino)-5-methyl thieno[2,3-dvpyrimidine-6-carboxylic acid N 0 N N O k 0 N VO Methyl 4-(2-(4-(tert-butoxycarbonylamino)butan-2yloxy)pyridin-3ylamino)-5-methyl 10 thieno[2,3-d]pyrimidine-6-carboxylate (600 mg) was dissolved in methanol (10 ml) and NaOH (1 M; 2.5 ml) was added. The reaction mixture was heated at reflux for 15 minutes. Then it was cooled to room temperature and HCI (1 M; 2.5 ml) was added. Methanol was evaporated and the residue was dissolved in dichloromethane. The mixture was washed with water, the organic layer was dried and concentrated in 15 vacuo. The residue was triturated with Et 2 0. Yield: 390 mg ESI mass spectrum: m/z = 474 (M+H)* 16. 2 4-(2-(4-aminobutan-2vloxv)pridin-3vlamino)-5-methylthieno[2,3-dlpvrimidine 20 6-carboxylate trifluoroacetate N 0 N 0 FF N F N 75 WO 2011/104340 PCT/EP2011/052813 Prepared analogously to example 1.2 from 4-(2-(4-(tert-butoxycarbonylamino)butan 2yloxy)pyridin-3ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid Yield: 100 mg ESI mass spectrum: m/z = 374 (M+H)* 5 Retention time HPLC: 1.12 min HPLC method: A_10 16.3 4-(2-(4-Aminobutan-2-vloxv)pvridin-3-vlamino)-N-(3-(dimethylamino)proipl)-5 methylthieno[2,3-dlpvrimidine-6-carboxamide bis (2,2,2-trifluoroacetate) 0 N 0 F F F F N 0 N 0 0 N~~ FF N S NF 10/ 4-(2-(4-(t-Butoxycarbonylamino)butan-2yloxy)pyridin-3ylamino)-5-methylthieno[2,3 d]pyrimidine-6-carboxylic acid (200mg) and HLnig's base (160 pl) was dissolved in THF (10 ml) and TBTU (148 mg) was added. To this mixture N,N-dimethyl propandiamine (58 pl) was added and the mixture was stirred at room temperature 15 for three days. The reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane. The organic layer was washed with water, dried and 3 ml conc. TFA was added. The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the product was purified by RP chromatography (Method amslpolar 1). 20 Yield: 190 mg ESI mass spectrum: m/z = 458 (M+H)* Retention time HPLC: 0.86 min HPLC method: A_10 25 Compound 16.4: 76 WO 2011/104340 PCT/EP2011/052813 Prepared analogously to example 16.3 using 4-(2-(4-(tert-butoxycarbonylamino) butan-2yloxy)pyridin-3ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia. Reten Structure Name Yield Mass tion method time 4-(2-(4-Amino o butan-2 N F yloxy)pyridin N F 3-ylamino)-5- 130m N methylthieno- 373 1.2 A_10 / 0 [2,3-d]pyrimi dine-6-carbox amide 2,2,2 trifluoroacetate 5 Compound 17 4-(2-(2-(Dimethylam ino)-2-oxoethoxy)-4-methylphenylamino)-5-methylth ieno[2, 3 dlpyrimidine-6-carboxylic acid 10 17.1 Ethyl 4-(2-(2-dimethylamino)-2-oxoethoxy)-4-methylphenylamino)-5 methyl -th ieno[2,3-dlipyrim id ine-6-carboxyl ate 0 N 00 N N S0 2-(2-Amino-5-methylphenoxy)-N,N-dimethylacetamide (300 mg) and ethyl 4-chloro-5 15 methyl-thieno[2,3-d]pyrimidine-6-carboxylate (447 mg) were dissolved in dioxane (5 ml) and p-toluenesulfonic acid monohydrate (44 mg) was added. The mixture was heated at 100 C for 1.5h. The reaction was allowed to cool to room temperature, the 77 WO 2011/104340 PCT/EP2011/052813 residue was dissolved in dichloromethane and extracted with water. The organic layer was dried and concentrated in vacuo. The residue was purified by chromatography (silica / dichloromethane: methanol 100-95:5). Yield: 114 mg 5 ESI mass spectrum: m/z = 377 (M+H)* 17.2 4-(2-(2-(Dimethylamino)-2-oxoethoxy)-4-methylphenylamino)-5-methyl thieno[2,3-dpyrimidine-6-carboxylic acid 0 N 00 N kN S 0 10 Ethyl 4-(2-(2-dimethylamino)-2-oxoethoxy)-4-methylphenylamino)-5-methyl thieno[2,3-d]pyrimidine-6-carboxylate (114 mg) was dissolved in methanol (5 ml) and aqueous NaOH (2M; 0.66 ml) was added. The reaction was stirred at room temperature for 4h. Then the reaction mixture was concentrated in vacuo and neutralisied with aqueous HCI (2M; 5 ml). The precipitate was filtered and the residue 15 was dissolved in DMF and purified by RP-chromatography (water with 0.2% trifluoroacetic acid/ methanol 72-100%) Yield: 26 mg ESI mass spectrum: m/z = 401 (M+H)* Retention time HPLC: 1.69 min 20 HPLC method: A_10 Compound 18 Methyl 4-(2-(1,3-diaminopropan-2-vloxy)-4-fluorophenylamino)-5-methylthieno[2,3 dlpyrimidine-6-carboxylate bis (2,2,2-trifluoroacetate) 25 18.1 4-{2-[2-tert-Butoxycarbonylamino-1 -(tert-butoxvcarbonylamino-methyl) ethoxyl-4-fl uoro-phenylamino}-5-methyl-thieno[2,3-dlpyrimid ine-6-carboxyl ic acid methyl ester 78 WO 2011/104340 PCT/EP2011/052813 N o >O N0 F 0 N 0 N I kN S /0 4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (2 g) and [2 (2-Amino-5-fluoro-phenoxy)-3-tert-butoxycarbonylamiino-propyl]-carbamic acid t-butyl (3.3 g) were dissolved in 20 ml isopropanol and 4.3 ml HLnig's base was added. The 5 reaction was heated to 1400C under microwave irradiation for 45 min. The reaction mixture was allowed to stand over the weekend and the resulting precipitate was filtered. The filter cake was purified by chromatography (silica / dichloromethane: methanol 50:1). Yield: 2 g 10 ESI mass spectrum: m/z = 606 (M+H)* Retention time HPLC: 2.34 min HPLC method: A_10 18.2 Methyl 4-(2-(1,3-diaminopropan-2-vloxy)-4-fluorophenylamino)-5 15 methylthieno[2,3-dpyrimidine-6-carboxylate bis (trifluoroacetate) 0 N N F F y0 F F 0 0 F F N 0 Prepared analogously to example 2.1 using 4-{2-[2-tert-Butoxycarbonylamino-1 -(tert butoxycarbonylamino-methyl)-ethoxy]-4-fluoro-phenylamino}-5-methyl-thieno[2,3 d]pyrimidine-6-carboxylic acid methyl ester 20 Yield: 2 g 79 WO 2011/104340 PCT/EP2011/052813 ESI mass spectrum: m/z = 406 (M+H)* Retention time HPLC: 0.87 min HPLC method: A_10 5 Compound 19 Methyl 4-(2-(1-acetamido-3aminopropan-2-vloxy)-4-fluorophenylamino)-5 methylth ieno[2,3-dlipyrim id ine-6-carboxyl ate (trifluoroacetate) 19.1 Methyl 4-(2-(1-acetamido-3-aminopropan-2-vloxy)-4-fluorophenylamino)-5 10 methylth ieno[2,3-dlipyri mid ine-6-carboxyl ate trifluoroacetate 0 N N 0 F 0 F N Methyl 4-(2-(1,3-diaminopropan-2-yloxy)-4-fluorophenylamino)-5-methylthieno[2,3 d]pyrimidine-6-carboxylate bis (trifluoroacetate) (150 mg) and triethylamine (0.1 ml) were dissolved in dichloromethane, acetylchloride (15pl) was added. The reaction 15 mixture was stirred at room temperature overnight. The reaction was diluted with dichloromethane and methanol and then extracted with aqueous HCI (1M). The organic layer was dried and concentrated in vacuo. The residue was purified by chromatography. The fractions were collected, concentrated in vacuo and triturated with Et 2 0. 20 Yield: 22 mg ESI mass spectrum: m/z = 448 (M+H)* Retention time HPLC: 1.35 min HPLC method: A_10 25 Further analogues of compound 19: The compounds listed in table 5 were synthesized analogously to example 19.1 using the appropriate amines and the corresponding chlorides. 80 WO 2011/104340 PCT/EP2011/052813 Table 5: Reten- HPLC Structure Name Yield Mass tion metho Chlorides time d 19. Methyl 4-(2-(1 2 amino-3 O (methyl N N 0sulfonamido)pr 0 opan-2-yloxy) F 0 F F 4-fluoro- 50 0 F 484 1.22 A_10 N phenylamino)- mg N 0 5 N S 0 methylthieno[2, 3-d]pyrimidine 6-carboxylate trifluoroacetate 19. 3 Methyl 4-(2 0 0 (1,3 N N diacetamidopro pan-2-yloxy)4 F 0 fluoro- 1 1 CI N phenylamino)- mg 490 1.51 A_10 N o 5 N S 0 methylthieno[2, 3-d]pyrimidine 6-carboxylate Compound 20 5 N-(3-(Dimethylamino)propyI)-4-(4-fIuoro-2-(4-hydroxy-4-methylpentan-2 Vloxv)phenylamino)-5-methyl-thieno[2,3-dlpyrimidine-6-carboxamide trifluoroacetate 20.1 Methyl 4-(4-fluoro-2-(4-hydroxy-4-methylpentan-2-vloxv)phenylamino)-5 methyl -th ieno[2,3-dlipyrim id ine-6-carboxyl ate 81 WO 2011/104340 PCT/EP2011/052813 0 F 0 N N 0 N S 0 4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (540 mg) and 4-(2-amino-5-fluorophenoxy)-2-methylpentan-2-ol (500 mg) were dissolved in dioxane (20 ml) and p-toluenesulfonic acid monohydrate (70 mg) was added. The 5 reaction was heated under reflux for 2h. Then the reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane and washed with water. The organic layer was separated, dried, filtered and evaporated. The residue triturated with methanol and the precipitate was filtered to give the intended product. 10 Yield: 710 mg ESI mass spectrum: m/z = 434 (M+H)' Retention time HPLC: 2.02 min HPLC method: A_9 15 20.2 4-(4-fluoro-2-(4-hydroxv-4-methylpentan-2-vloxv)phenvlamino)-5-methyl thieno[2,3-dlpvrimidine-6-carboxylic acid F 0 N0 kN S 0 Methyl 4-(4-fluoro-2-(4-hydroxy-4-methylpentan-2-yloxy)phenylamino)-5-methyl thieno[2,3-d]pyrimidine-6-carboxylate (710 mg) was dissolved in methanol (50 ml) 20 and aqueous NaOH (4M; 5ml) was added. The reaction was stirred at room temperature overnight and then heated at 600C for 2h. Finally the solution was neutralised and concentrated in vacuo. The residue was triturated with water. The resultant precipitate was filtered and dried. 82 WO 2011/104340 PCT/EP2011/052813 Yield: 600 mg ESI mass spectrum: m/z = 420 (M+H)* Retention time HPLC: 1.75 min HPLC method: A_9 5 20.3 N-(3-(Dimethylamino)propyl)-4-(4-fluoro-2-(4-hydroxv-4-methylpentan-2 vloxv)phenvlamino)-5-methyl-thieno[2,3-dlpvrimidine-6-carboxamide trifluoroacetate 00 F 0 01y F FF F N NN / N 10 4-(4-Fluoro-2-(4-hydroxy-4-methylpentan-2-yloxy)phenylamino)-5-methyl-thieno[2,3 d]pyrimidine-6-carboxylic acid (100 mg) was dissolved in DMF (5 ml) and triethylamine (75 pl) was added. Then TBTU (80 mg) was added and the reaction was stirred for 5 minutes. Followed by N,N-dimethyl-1,3-propanediamine (35 pl) the reaction mixture was stirred at room temperature for 2h. An further aliquot of N,N 15 dimethyl-1,3-propanediamine and TBTU (40 mg) was added. The mixture was heated at 600C and stirred for 2h. Then the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane and washed with soda solution. The organic phase was purified by RP-chromatography (water with 0.2% trifluoroacetic acid/ methanol 72-100%). 20 Yield: 132 mg ESI mass spectrum: m/z = 504 (M+H)* Retention time HPLC: 1.18 min HPLC method: A_9 25 Compound 21 83 WO 2011/104340 PCT/EP2011/052813 5-Methyl-4-(2-(1,1 1-triflouropropan-2vloxv)pyridin-3-vlamino)thieno[2,3-dlpyrimidine 6-carboxamide 21.1 Methyl 5-methyl-4-(2-(1,1,1-trifluoropropan-2vloxv)pyridin-3 5 vlamino)thieno[2,3-dpyrimidine-6-carboxylate F N 0 F N F N 0 kN S 0 Prepared analogously to example 1.1 by heating under microwave irradiation at 110 C using 2-(1,1,1 -trifluoropropan-2-yloxy)pyridin-3-amine and 4-Chloro-5-methyl thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester 10 Yield: 270 mg ESI mass spectrum: m/z = 413 (M+H)* Retention time HPLC: 3.37 min HPLC method: AC 1 15 21.2 5-Methyl-4-(2-(1,1 1 -trifluoropropan-2vloxv)pyridin-3-ylamino)thieno[2,3 dlpyrimidine-6-carboxylic acid F N ,0

-

F N F N10 kN S 0 Prepared analogously to example 1.2 using Methyl 5-methyl-4-(2-( 1,1 trifluoropropan-2yloxy)pyridin-3-ylamino)thieno[2,3-d]pyrimid ine-6-carboxylate 20 Yield: 278 mg ESI mass spectrum: m/z = 399 (M+H)* Retention time HPLC: 3.25 min HPLC method: AC 1 84 WO 2011/104340 PCT/EP2011/052813 21.3 5-Methyl-4-(2-(1,1 1-trifluoropropan-2vloxv)pvridin-3-vlamino)thieno[2,3 dIpyrimid ine-6-carboxamide F N O F N F N N N S 0 5-Methyl-4-(2-(1 1,1 -trifluoropropan-2yloxy)pyridin-3-ylamino)thieno[2,3-d]pyrimidine 5 6-carboxylic acid (278 mg), HATU (320 mg) and HLnig's Base (144 pl) were dissolved in DMF (6.5 ml) at 00C. The reaction was stirred for 30 minutes after this time NH 3 in dioxane (0.5 M; 5.3 ml) was added. The reaction was allowed to warm to room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was extracted with dichloromethane and water. The organic layer was 10 separated, dried and evaporated. The crude product was purified by chromatography (silica / dichloromethane: methanol: NH 3 90:10:1). Yield: 124 mg ESI mass spectrum: m/z = 398 (M+H)' Retention time HPLC: 3.93 min 15 HPLC method: AC 1 Further analogues of example 21: Prepared analogously to example 21.3 using 5-methyl-4-(2-(1,1,1-trifluoropropan 2yloxy)pyridin-3-ylamino)thieno[2,3-d]pyrimidine-6-carboxylic acid and the 20 corresponding amine Reten HPLC Structure Name Yield Mass tion Amine method time 21. 5-methyl-N-(1 4 N O F methylpiperidin-4 F N N134 N trifluoropropan-2- 495 2.23 A_1 N N S O yloxy)pyridin-3 ylamino)thieno[2,3 d]pyrrimidine-6 85 WO 2011/104340 PCT/EP2011/052813 carboxamide 21. N-(3-(dimethyl N 0 F amino)propyl)-5- N N F methyl-4-(2-(1,1,1- 100 S N N- trifluoro-propan-2- 483 2.25 A_1 I N yloxy)-pyridin-3-yl- 9g N S 0 amino)thieno[2,3 d]pyrimidine-6 carboxamide 21. N-Methyl-5-methyl 4-(2-(1 ,1, 1-trifluoro N O propan-2-yloxy) -F N pyridin-3-yl- 412 3.05 A_1 N N N amino)thieno[2,3- mg N s 0 d]pyrimidine-6-N methylcarbox amide 21. 5-Methyl-4-[2 (2,2,2-trifluoro-1 N F metyhl-ethoxy)- N F N pyridin-3-ylamino]- 207 NN tin[,-493 2.25 AC 1 / N thieno[2,3- m N S 0 d]pyrimidine-6-

/N

carboxylic acid (4 dimethylamino-but 2-ynyl)-amide 21. 5-Methyl-4-[2 8 (2,2,2-trifluoro-1 F metyhl-ethoxy) N 0 IN NO F F pyridin-3-ylamino]- 150 N N N. ten2,-442 2.78 AC 1 N IN -- O thieno[2,3- mg 0 N S Od]pyrimidine-6 carboxylic acid (4 hydroxy-ethyl) amide Compound 22 86 WO 2011/104340 PCT/EP2011/052813 4-(2-(1,3-Diethoxvpropan-2-vloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3 d pyrimid ine-6-carboxamide 22.1 Methyl 4-(2-(1,3-diethoxvpropan-2-vloxy)-4-fluorophenylamino)-5-methyl 5 thieno[2,3-dpyrimidine-6-carboxylate o 0 0 F 0 N N 0 N S 0 Prepared analogously to example 18.1 using 4-Chloro-5-methyl-thieno[2,3 d]pyrimidine-6-carboxylic acid methyl ester and 2-(1,3-diethoxypropan-2-yloxy)-4 fluoroaniline. 10 The solvent dioxane was used instead of isopropanol and p-toluonesulfonic acid monohydrate was added. Yield: 590 mg ESI mass spectrum: m/z = 464 (M+H)* Retention time HPLC: 3.75 min 15 HPLC method: A_10 22.2 4-(2-(1,3-Diethoxvpropan-2-vloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3 dlpyrimidine-6-carboxylic acid

K

0 0 F 0 N 0 20 N 0 87 WO 2011/104340 PCT/EP2011/052813 Prepared analogously to example 1.2 using methyl 4-(2-(1,3-diethoxypropan-2 yloxy)-4-fluorophenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid. The reaction was performed at 800C. Yield: 390 mg 5 ESI mass spectrum: m/z = 450 (M+H)* Retention time HPLC: 1.91 min HPLC method: A_10 22.3 4-(2-(1,3-Diethoxvpropan-2-vloxv)-4-fluorophenvlamino)-5-methylthieno[2,3 10 dvpyrimidine-6-carboxamide 0 N O N S N 4-(2-(1,3-Diethoxypropan-2-yloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3 d]pyrimidine-6-carboxylic acid (150 mg), TBTU (107, 2 mg) and Honig's base (122 pl) were dissolved in THF (10 ml), ammonia (0,5M; 700pl) was added and the 15 mixture was stirred at room temperature overnight. Then it was evaporated and the residue dissolved in dichloromethane. The mixture was extracted with water and aqueous NaOH (0.5M). The organic layer was dried and concentrated in vacuo. The residue was triturated with Et 2 O and a few drops of ethanol. Yield: 105 mg 20 ESI mass spectrum: m/z = 449 (M+H)* Retention time HPLC: 2.02 min HPLC method: A_10 Compound 23 25 4-(2-(1,3-Difluoropropan-2-vloxy)-4-fluorophenvlamino)-5-methyl-thieno[2,3 dlpyrimidine-6-carboxamide 88 WO 2011/104340 PCT/EP2011/052813 23.1 Methyl 4-(2-(1,3-difluoropropan-2-vloxy)-4-fluorophenylamino)-5-methyl th ieno[2,3-dpyrimid ine-6-carboxylate F F O N N 0 N) S 0 Prepared analogously to example 21.1 using 2-(1,3-difluoropropan-2-yloxy)-4 5 fluoroaniline and 4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxyl ic acid methyl ester. Yield: 3.7 g ESI mass spectrum: m/z = 412 (M+H)* Retention time HPLC: 3.37 min 10 HPLC method: AC 1 23.2 4-(2-(1,3-Difluoroiproipan-2-vloxv)-4-fluoroiphenvlamino)-5-methyl-thieno[2,3 dlpyrimidine-6-carboxylic acid F F O N N 0 kN S 0 15 Prepared analogously to example 1.2 using methyl 4-(2-(1,3-difluoropropan-2-yloxy) 4-fl uorophenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate Yield: 1.93 g ESI mass spectrum: m/z = 398 (M+H)* Retention time HPLC: 2.93 min 20 HPLC method: AC 1 23.3 4-(2-(1,3-Difluoropropan-2-vloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3 d pyrimid ine-6-carboxamide 89 WO 2011/104340 PCT/EP2011/052813 F F O N kN S 0 Prepared analogously to example 21.3 using 4-(2-(1,3-Difluoropropan-2-yloxy)-4 fluorophenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid Yield: 180 mg 5 ESI mass spectrum: m/z = 397 (M+H)* Retention time HPLC: 2.70 min HPLC method: AC 1 Further analogues of compound 23 10 The compounds listed in Table 6 were synthesized analogously to example 23.3 using 4-(2-(1,3-Difluoropropan-2-yloxy)-4-fluorophenylamino)-5-methylthieno[2,3 d]pyrimidine-6-carboxylic acid and the corresponding amine. Table 6: Reten HPLC Structure Name yield Mass tion method time 23.4 F 4-(2-(1,3-difluoro F propan-2-yloxy)-4 F fluorophenylamino)- 50 411 2.77 AC1 N N,5-dimethylthieno mg [2,3d]pyrimidine-6 N S 0 carboxamide 23.5 F Tert-butyl (1 R,2R)-2-(4 F O 2(1,3-difluoro-propan- 134 N N 0 [2,3-d] pyrimidine-6- 522 3.05 AC1 N -\N"carboxamido) mg N S 0 cyclopropyl carbamate 90 WO 2011/104340 PCT/EP2011/052813 23.6 4-(2-(1,3-difluoro propan-2-yloxy)-4 F fluorophenylamino) F O F N-(3-(dimethylamino)- 78 N propyl)-5-methyl- 482 2.10 AC1 N N thieno[2,3-d] N S O pyrimidine-6 carboxamide 23.7 4-(2-(1,3-difluoro F propan-2-yloxy)-4 F fluorophenylamino) N-(2-(dimethylamino)- 102 N 468 2.14 AC1 N ethyl)-5-methylthieno- mg N O N [2,3-d]-pyrimidine-6 N S 0 carboxamide 23.8 4-(2-(1,3-difluoro F propan-2-yloxy)-4 F O F fluorophenylamino) N-(2-(hydroxyethyl)-5- 75 N 0 methylthieno[2,3-d] mg pyrimidine-6 N S 0 carboxamide 23.9 4-(2-(1,3-difluoro F propan-2-yloxy)-4 F O F fluorophenylamino) a N N-(4-(dimethylamino)- 56 492 2.16 ACl N N but-2ynyl) 5-methyl- mg N S 0 thieno[2,3-d]pyrimidine 6-carboxamide 23.1 F 4-(2-(1,3-difluoro 0F propan-2-yloxy)-4 fluorophenylamino)-5- 92 N methyl-N-(3-(pyrrolidin- 508 2.17 AC1 1-yl)propyl)thieno[2,3- g N S 0 d]pyrimidine-6 carboxamide 91 WO 2011/104340 PCT/EP2011/052813 Compound 24 4-(2-(1,3-Difluoropropan-2-vloxy)-4-fluorophenylamino)-5-methyl-N (methylsulfony)thieno[2,3-dlpyrimidine-6-carboxamide F F O 5 N N 4-(2-(1,3-Difluoropropan-2-yloxy)-4-fluorophenylamino)-5-methylthieno[2,3 d]pyrimidine-6-carboxylic acid (197 mg), 4-dimethylaminopyridine (76 mg) and 1 ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (125 mg) was dissolved in dichloromethane (20 ml). Methanesulfonamide (59.5 mg) was added and the 10 reaction was stirred at room temperature for about 24h. The mixture was washed with a KHSO 4 solution. The organic layer was separated, dried and concentrated in vacuo. The residue was purified by chromatography (dichloromethane: methanol:

NH

3 80:20:1). The fractions were collected and triturated with diisopropyl ether. Yield: 57 mg 15 ESI mass spectrum: m/z = 475 (M+H)' Retention time HPLC: 3.11 min HPLC method: AC 1 Compound 25 20 N-((trans)-2-Aminocyclopropyl)-4-(2-(1,3-difluoropropan-2-vloxy)-4 fluoroiphenylamino)-5-methylthieno[2,3-dlpyrimidine-6-carboxamide hydrochloride F F OCI CI N N" N N S 0 tert-Butyl (trans)-2-(4-(2-(1,3-difluoropropan[2,3-d]pyrimidine-6-carboxamido)cyclo propyl carbamate (130 mg) was dissolved in dioxane (8 ml) and a solution of HCI in 92 WO 2011/104340 PCT/EP2011/052813 dioxane (4M; 1.34 ml) was added. The reaction was stirred at room temperature overnight. Diethyl ether was added and the precipitate was filtered and washed with Et 2 O to give the title compound. Yield: 97 mg 5 ESI mass spectrum: m/z = 452 (M+H)* Retention time HPLC: 2.10 min HPLC method: AC 1 Compound 26 10 N-(3-(Dimethylamino)prolpyl-4-(4-fluoro-2-((tetrahydro-2-H-Iyran-4 vI)methoxv)phenylamino)-5-methyl-thieno[2,3-dlpyrimidine-6-carboxamide 26. 1 Methyl-4-(4-fluoro-2-((tetrahydro-2-H-ipran-4-vl)methoxv)phenylamino)-5 methyl -th ieno[2,3-dlipyrim id ine-6-carboxyl ate F 0 N N 0

LK-

15 N S 0 Methyl 4-(4-fluoro-2-hydroxyphenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6 carboxylate (100 mg) was dissolved in DMF (2 ml), 4-bromomethyltetrahydropyran (107 mg) and potassium carbonate (83 mg) were added. The reaction was stirred at 600C overnight. Then the reaction mixture was diluted with EtOAc and washed with 20 water and brine. The solvent was removed in vacuo and the residue triturated with Et 2 0. Yield: 130 mg ESI mass spectrum: m/z = 432 (M+H)* 25 26. 2 4-(4-Fluoro-2-((tetrahydro-2-H-ipran-4-vl)methoxv)phenylamino)-5-methyl thieno[2,3-dlpyrimidine-6-carboxylic acid 93 WO 2011/104340 PCT/EP2011/052813 O F 0 N 0 N I kN S 0 Methyl-4-(4-fl uoro-2-((tetrahydro-2-H-pyran-4-yl)methoxy)phenylamino)-5 methylthieno[2,3-d]pyrimidine-6-carboxylate (82 mg) and NaOH (2M; 0.5 ml) was 5 dissolved in ethanol (2 ml). The reaction was stirred at room temperature overnight. Then the reaction mixture was diluted with dichloromethane and HCI (2M). The suspension was filtered, washed with brine and ether. The residue was dried in vacuo over P 2 0 5 . Yield: 41 mg 10 26.3 N-(3-(Dimethylamino)proipl-4-(4-fluoro-2-((tetrahvdro-2-H-pyran-4 vI)methoxv)phenvlamino)-5-methyl-thieno[2,3-dlpvrimidine-6-carboxamide 0 F 0 N O NS NN 15 HATU (36 mg) was added to a solution of 4-(4-fluoro-2-((tetrahydro-2-H-pyran-4 yl)methoxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid (36mg) and DIPEA (17 pl) in DMF (1 ml). The reaction mixture was stirred for 40min at room temperature. Then 3-(dimethylamino)propylamine (49 pl) was added. The reaction 20 mixture was stirred at room temparture overnight. It was diluted with EtOAc and washed with water and brine. The organic phase was concentrated in vacuo. The residue was suspended in Et 2 O and filtered and dried. 94 WO 2011/104340 PCT/EP2011/052813 Yield: 40 mg ESI mass spectrum: m/z = 502 (M+H)* 5 Example 27 4-(2-(2-Fluoropropoxv)pyridin-3-vlamino)-N-(2-hydroxvethyl)-5-methylthieno[2,3 dIpyrimid ine-6-carboxamide 27. 1 Methyl-4-(2-(2-fluoropropoxv)ipridin-3-vlamino)-5-methyl-thieno[2,3 10 dpyrimidine-6-carboxylate F N 0 1O N N 0 N S 0 2-(2-Fluoropropoxy)pyridin-3-amine (153 mg) was dissolved in dioxane (30 ml), 4 Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (174.54 mg) and HCI in dioxane (4M; 25 pl) was added. The reactin was stirred at 600C for three 15 days. The reaction was concentrated in vacuo. Yield: 333 mg Retention time HPLC: 2.37 min HPLC method: 002_CCZQ4 20 27. 2 4-(2-(2-Fluoropropoxvpyridin-3-vlamino)-5-methyl-thieno[2,3-dpyrimidine-6 carboxylic acid F N 0 N N 0 95 WO 2011/104340 PCT/EP2011/052813 To a solution of methyl-4-(2-(2-fluoropropoxy)pyridin-3-ylamino)-5-methyl-thieno[2,3 d]pyrimidine-6-carboxylate (333 mg) in THF (10 ml) was added lithium hydroxide (1 M; 8 ml) and the reaction stirred at room temperature overnight. The mixture was neutralized with HCI (1 M; 8 ml) and concentrated in vacuo. The crude product was 5 purified by chromatography. Yield: 196 mg ESI mass spectrum: m/z = 363 (M+H)* Retention time HPLC: 1.91 min HPLC method: 003_CCZQ7 10 27.3 4-(2-(2-Fluoropropoxv)ipridin-3-vlamino)-N-(2-hydroxvethyl)-5 methyl-thieno[2,3-dlpvrimidine-6-carboxamide F N 0 N N 0 N N 4-(2-(2-Fl uoropropoxy)pyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimid ine-6 15 carboxylic acid (36.2 mg), HATU (42 mg) and HLnig's base (34 pl) were dissolved in DMF (2 ml) and ethanolamine (9 pl) was added. The reaction was stirred at room temperature for 2h. The reaction mixture was purified directly by chromatography. Yield: 31mg ESI mass spectrum: m/z = 406 (M+H)* 20 Retention time HPLC: 2.09 min HPLC method: 004_CCZQ6 Compound 77.4: Prepared analogously to example 27.3 using 4-(2-(2-Fluoropropoxy)pyridin-3 25 ylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and the corresponding amine. Structure Name Yield Mass Reten- HPLC amine 96 WO 2011/104340 PCT/EP2011/052813 tion time method N-(3-(dimethylamino) F propyl)-4-(2-(2-fluoro N O propoxy)pyridin-3- 26 004C 0 ylamino)-5-methyl- 447 1.75 N S N- thieno[2,3-d]pyrimidine- mg C_ZQ6 NH, N- 6-carboxamide hydrochloride Compound 28 4-(2-(2-Methoxvpropan-2-vloxv)pvridin-3-vlamino)-5-methylthieno[2,3-dlpvrimidine-6 carboxamide 5 28. 1 Methyl-4-(2-(1-methoxvpropan-2-vloxv)pvridin-3-vlamino)-5-methyl-thieno[2,3 dlpyrimidine-6-carboxylate N 0 N N 0 N S 0 Prepared analogously to example 27.1 10 Yield: 344 mg Retention time HPLC: 2.40 min HPLC method: 002_CCZQ4 28. 2 4-(2-(1-Methoxvpropan-2-vloxv)pvridin-3-vlamino)-5-methylthieno[2.,3 15 dpyrimidine-6-carboxylic acid N 0 N 9 0 N \ 0 97 WO 2011/104340 PCT/EP2011/052813 Prepared analogously to example 27.2 using methyl-4-(2-(1 -methoxypropan-2 yloxy)pyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate Yield: 119 mg ESI mass spectrum: m/z = 375 (M+H)* 5 Retention time HPLC: 1.90 min HPLC method: 003_CCZQ7 28. 3 4-(2-(2-Methoxvpropan-2-vloxv)pvridin-3-vlamino)-5-methyl-thieno[2,3 dIpyrimid ine-6-carboxamide N 0 N 10 N 10 N S N Prepared analogously to example 27.3 using 4-(2-(1 -methoxypropan-2-yloxy)pyridin 3-ylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (37 mg) and ammonia in dioxane (0.5M; 2 ml) Yield: 23 mg 15 ESI mass spectrum: m/z = 374 (M+H)* Retention time HPLC: 2.13 min HPLC method: 004_CCZQ6 Further analogues of 28: 20 Prepared analogously to example 29.3 using 4-(2-(1 -methoxypropan-2-yloxy)pyridin 3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid and the corresponding amine Reten- HPLC Structure Name Yield Mass Amine tion time method 98 WO 2011/104340 PCT/EP2011/052813 28. N-(2-hydroxy 4 ethyl)-4-(2-(1 methoxy N 0 propan-2 N yloxy)pyridin- 16 004_C OH 418 2.11 N 0 3-ylamino)-5- mg C_ZQ6 H 2 N N S N methylthieno _0 [2,3-d] pyrimidine-6 carbox-amide 28. N-(3-(di 5 methylamino) propyl)-4-(2 o (1-methoxy N O propan-2- N N yloxy)pyridin- 30 004_C N o459 1.75 LN S N 3-ylamino)-5- mg C_ZQ6 N N- methlthieno[2, 3-d]pyrimi dine-6 carboxamide hydrochloride Compound 29 4-(2-(2-Hydroxvethoxv)pvrid in-3-vlamino)-5-methyl-th ieno[2,3-djpyrim id ine-6 carboxamide 5 29. 1 Methyl-4-(2-(2-hydroxvethoxv)ipvridin-3-vlamino)-5-methyl-thieno[2,3 dlpyrimidine-6-carboxylate OH N 0 NH 0 N S 0 99 WO 2011/104340 PCT/EP2011/052813 Prepared analogously to example 28.1 from 2-(3-aminopyridin-2-yloxy)ethano (175 mg) and chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (121 mg) Yield: 475 mg 5 Retention time HPLC: 2.18 min HPLC method: 002_CCZQ4 29. 2 4-(2-(2-Hydroxvethoxv)pvridin-3-vlamino)-5-methyl-thieno[2,3-dlpyrimidine-6 carboxylic acid OH N 0 NH 0 10 N S OH Prepared analogously to example 28.1 from methyl-4-(2-(2-hydroxyethoxy)pyridin-3 ylamino)-5-methyl-thieno[2,3-d]pyrimid ine-6-carboxylate Yield: 61 mg Retention time HPLC: 2.14 min 15 HPLC method: 003_CCZQ7 29. 3 4-(2-(2-Hydroxvethoxv)pvridin-3-vlamino)-5-methylthieno[2,3-dlpvrimidine-6 carboxamide OH N 0 NH N 0 NNH kN S

NH

2 20 Prepared analogously to example 28.3 using 4-(2-(2-hydroxyethoxy)pyridin-3 ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid (30.5mg) and ammonia in dioxane (0.5M; 1.6 ml) Yield: 13 mg 100 WO 2011/104340 PCT/EP2011/052813 ESI mass spectrum: m/z = 346 (M+H)* Retention time HPLC: 1.87 min HPLC method: 004_CCZQ6 5 Compound 29.4: Prepared analogously to example 29.3 using 4-(2-(2-hydroxyethoxy)pyridin-3 ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid and the corresponding amine Reten HPLC Structure Name Yield Mass tion amin method time OH N-(3-(dimethyl amino)propyl)-4 N O (2-(2-hydroxy- N NH ethoxy)pyridin-3- 26 004_CC_ NNH ylamino)-5- 431 1.54 N N S N methylthieno[2,3 H N- d]pyrimidine-6 carboxamide hydrochloride 10 Compound 30 4-(2-(2,2-Difluoroethoxv)ipridin-3-vlamino)-5-methyl-thieno[2,3-dlpvrimidine-6 carboxamide 15 30. 1 Methyl-4-(2-(2,2-difluoroethoxv)pvridin-3-vlamino)-5-methyl-thieno[2,3 dI pyrim id ine-6-carboxyl ate F F N 0 N N 0 N S 0 101 WO 2011/104340 PCT/EP2011/052813 Prepared analogously to example 28.1 from 2-(2,2-Difluoroethoxy)pyridin-3-amine (171 mg) and Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (190 mg) Yield: 376 mg 5 Retention time HPLC: 2.35min HPLC method: 002_CCZQ4 30. 2 4-(2-(2,2-Difluoroethoxv)ipridin-3-vlamino)-5-methylthieno[2,3-d1pyrimidine-6 carboxylic acid F F N 0 N 1 0 10 N S 0 Prepared analogously to example 28.2 using methyl-4-(2-(2,2-difluoroethoxy)pyridin 3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (376 mg). Yield: 220 mg ESI mass spectrum: m/z = 367 (M+H)* 15 Retention time HPLC: 1.91 min HPLC method: 007_CCZQ7 30. 3 4-(2-(2,2-Difluoroethoxv)ipridin-3-vlamino)-5-methyl-thieno[2,3-dlpvrimidine-6 carboxamide F F N 0 N 200 20 N S N Prepared analogously to example 28.3 from 4-(2-(2,2-difluoroethoxy)pyridin-3 ylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (36.6mg) and ammonia in dioxane (0.5M; 2 ml). 102 WO 2011/104340 PCT/EP2011/052813 Yield: 18mg ESI mass spectrum: m/z = 366 (M+H)* Retention time HPLC: 2.09min HPLC method: 004_CCZQ6 5 Further analogues of 30: Prepared analogously to example 30.3 from 4-(2-(2,2-Difluoroethoxy)pyridin-3 ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid and the corresponding amine 10 Reten- HPLC Structure Name Yield Mass tion time method amine 30.4 F 4-(2-(2,2 difluoroethox F 0 y)pyridin-3 N 0 ylamino)-N- NH N (2-hydroxy- 29 004_C N2 0 ethyl)-5- 410 2.06 methylthieno mg C_ZQ6 N S N- [2,3-d]pyrimi dine-6 carboxamide 30.5 F 4-(2-(2,2 F difluoroethox N 0 y)pyridin-3 ylamino)-N- 20M N (3-(dimethyl- 12 004_C N 0 amino)propyl 451 1.71 )-5-methyl- mg CZQ6 N N S N thieno[2,3 N d]pyrimidine 6-carbox amide hydro chloride 25 Compound 31 4-(2-(1 -(Ethylamino)-1 -oxopropan-2-vloxv)-4-fluorophenvlamino)-5-methyl-thieno[2,3 dIpyrimid ine-6-carboxamide 31. 1 Methyl-4-(2-(1-tert-butoxy-1-oxopropan-2-vloxv)-4-fluorophenvlamino)-5 30 methyl-thieno[2,3-dvpyrimidine-6-carboxylate 103 WO 2011/104340 PCT/EP2011/052813 0,1 F 0 N N 0 N S 0 Methyl 4-(4-fluoro-2-hydroxyphenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6 carboxylate (100 mg) and Caesium carbonate (240 mg) was dissolved in acetonitrile (2 ml) and 2-bromopropionic acid tert-butylester (70 mg) was added. The reaction 5 mixture was stirred at 600C for 2h. Then the reaction was quenched with water and the precipitate was collected by filtration. The residue cake was washed with water and a few drops of methanol. Yield: 103 mg ESI mass spectrum: m/z = 462 (M+H)* 10 31. 2 2-(5-Fluoro-2-(6-(methoxvcarbonvl)-5-methylthieno[2,3-dlpvrimidin-4 vlamino)phenoxv)propanoic acid 0 051 F 0 N s 0 kN S 0 Prepared analogously to example 8.1 using methyl-4-(2-(1 -tert-butoxy-1 -oxopropan 15 2-yloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (2.1 g) and 50% trifluoroacetic acid in dichloromethane (20 ml). Yield: 1.9 g ESI mass spectrum: m/z = 406 (M+H)* Retention time HPLC: 1.96 min 20 HPLC method: A_9 104 WO 2011/104340 PCT/EP2011/052813 31. 3 Methyl 4-(2-(1-(ethylamino)-1-oxopropan-2-vloxy)-4-fluorophenylamino)-5 methylth ieno[2,3-dlipyrim id ine-6-carboxyl ate N 0-510 F aO N N S 0 To a solution of 2-(5-fluoro-2-(6-(methoxycarbonyl)-5-methy-thieno[2,3-d]pyrimidin-4 5 ylamino)phenoxy)propanoic acid (500 mg) and TBTU (400mg) in acetonitrile (10 ml) was added triethylamine (430 pl). The mixture was stirred for 20 min. Then ethylamine (2M; 1.5 ml) was added and the mixture was stirred at room temperature overnight. Then the reaction mixture was diluted with methanol and purified by chromatography. 10 Yield: 360 mg ESI mass spectrum: m/z = 433 (M+H)* Retention time HPLC: 1.89 min HPLC method: A_ 9 15 31. 4 4-(2-(1 -(Ethylamino)-1 -oxopropan-2-vloxy)-4-fluorophenylamino)-5-methyl thieno[2,3-dipyrimidine-6-carboxylic acid N F O11 N kN S 0 Prepared analogously to example 1.2 from methyl 4-(2-(1 -(ethylamino)-1 -oxopropan 2-yloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (360 20 mg). The reaction stirred at 500C overnight. 105 WO 2011/104340 PCT/EP2011/052813 Yield: 299 mg ESI mass spectrum: m/z = 419 (M+H)* Retention time HPLC: 2.65 min HPLC method: A_4 5 31. 5 4-(2-(1 -(Ethylamino)-1 -oxopropan-2-vloxv)-4-fluorophenvlamino)-5-methyl tieno[2,3-dvpyrimidine-6-carboxamide N 0-I F 0 N N 0 kN S N Prepared analogously to example 1.3 using 4-(2-(1-(ethylamino)-1-oxopropan-2 10 yloxy)-4-fluorophenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid (60 mg) and ammonia in THF (0.5 M; 600pl). Yield: 25 mg ESI mass spectrum: m/z = 418 (M+H)* Retention time HPLC: 1.41 min 15 HPLC method: A_9 Further analogues to 31: Prepared analogously to example 32.5 from the corresponding amine and 4-(2-(1 (ethylamino)-1 -oxopropan-2-yloxy)-4-fluorophenylamino)-5-methylthieno[2,3 20 d]pyrimidine-6-carboxylic acid Reten HPLC Structure Name Yield Mass tion method amine time 106 WO 2011/104340 PCT/EP2011/052813 31.6 4-(2-(1 (ethylamino) 1-oxo N propan-2 0 _Yyloxy)-4 F fluorophenyla 30 o mino)-N,5- 432 1.65 A_9 N N dimethyl- 9 o thieno[2,3 d]pyrimidine N S N 6-carbox amide 31.7 N-(3-(di N methylamino) propyl)-4-(2 0_ (1-(ethyl Fs O amino)-1- N oxo-propan- 32 N 2-yloxy)-4- 503 1.97 A 9 N 0 fluorophenyla mg N N S N- mino)-5 methylthieno[ N_ 2,3-d]pyrimi ci dine-6 carboxamide hydrochloride Compound 32 Methyl 4-(2-(1-(2-(dimethylamino)ethylamino)-1-oxopropan-2-vloxy)-4 fluorophenylam ino)-5-methyl-th ieno[2,3-dpyrim id ine-6-carboxylate 5 32. 1 Methyl 4-(2-(1-(2-(dimethylamino)ethylamino)-1 -oxopropan-2-vloxv)-4 fluorophenylam ino)-5-methyl-th ieno[2,3-dpyrim id ine-6-carboxylate N N 0. , F 0 N N 0 N S 0 Prepared analogously to example 32.3 from 2-(5-fluoro-2-(6-(methoxycarbonyl)-5 10 methylthieno[2,3-d]pyrimidin-4-ylamino)phenoxy)propanoic acid (200 mg) and 2 dimethylaminoethylamine (70 pl) 107 WO 2011/104340 PCT/EP2011/052813 Yield: 136 mg ESI mass spectrum: m/z = 476 (M+H)' Retention time HPLC: 2.17 min HPLC method: A_4 5 Compounds 32.2- 32.35: Step 1 Methyl 4-(4-fluoro-2-hydroxyphenylamino)-5-methylthieno[2,3-d]pyrimidine-6 carboxylate (667 mg) and the corresponding alcohol (e.g ethylen glycol 3eq = 372 10 mg) were dissolved in THF (30 ml). Under a nitrogen atmosphere triphenylphosphine (1.1 g) and diisopropyl azodicarboxylate (844 pl) were added and the reaction was stirred at room temperature for three days. An additional aliqout of the alcohol, diisopropyl azodicarboxylate and triphenylphosphine was added and the reaction was stirred overnight. Then the reaction mixture was filtered and washed with 15 dichloromethane: methanol 9:1. The filtrate was concentrated in vacuo and the residue was purified by chromatography to give the intermediate esters R1 N N S 0 Step 2: 20 The intermediate esters (step 1) were dissolved in a mixture of methanol (10 ml)/ THF (5 ml) and NaOH (1 M; 5ml) was added. The reaction was stirred at room temperature for three days. The solvent was concentrated in vacuo and the residue was neutralized with HCI (1 M; 5ml) and the precipitate was collected by filtration. The residue cake was dried, suspended in acetonitrile, acidified with HCI and 25 concentrated in vacuo to give the intermediate acids (a-1) 108 WO 2011/104340 PCT/EP2011/052813 F 0,a FR1 N N S 0 Interme Final Retention HPLC diate R1 compound product time method 32.2 a 0, N 2.69 004_CCZQ7 F F 32.3 b 0 2.42 004_CCZQ6 F F 32.4 C F 2.76 004_CCZQ7 F 32.5 d 0 FF 2.47 004_CCZQ7 011 32.6 e F 2.8 004_CC_ZQ7 0 F 32.7 f 2.82 004_CCZQ7 0 32.8 g 0 2.55 004_CCZQ7 0 32.9 h 2.62 004_CCZQ7 0 01-1 32.10 i 2.86 004_CCZQ7 0 109 WO 2011/104340 PCT/EP2011/052813 F F F 32.11 2.79 004_CCZQ7 0 F 32.12 k 2.82 004_CCZQ7 0 32.13 I F 2.68 003 CC ZQ7 O F Step 3 The acid a and HLnig's base ( 2 5pl) was dissolved in DMF (3 ml). After a few minutes HATU (42 mg) was added. To this mixture N,N- dimethyl-1,3-propanediamine (19 pl) 5 was added. The reaction mixture was stirred at room temperature overnight. The mixture was purified by chromatography to yield compound 35. F R1 R2 10 The following compounds were synthesized in an analogue manner: Inter me Final Retention date NR2R3 Mass HPLC method compound time pro duct 32.14 a 456 1.98 002_CCZQ4 H 32.15 a 497 1.76 002_CCZQ4 110 WO 2011/104340 PCT/EP2011/052813 32.16 b 486 1.78 002_CCZQ4 H 32.17 c H 383 2.01 002_CCZQ4 H 32.18 c 1 427 2.00 002_CCZQ4 H 32.19 c 468 1.77 002_CCZQ4 32.20 d H 453 2.07 002_CCZQ4 H 32.21 d 409 2.07 002_CCZQ4 H 32.22 d H 494 1.82 002_CCZQ4 32.23 e N 453 2.02 002_CCZQ4 H 32.24 e 494 1.79 002_CCZQ4 H 32.25 e'N408 2.04 002_CCZQ4 H 32.26 f H 464 1.80 002_CCZQ4 32.27 g N 422 2.03 002_CC_ZQ4 H K111 32.28 f 1N 378 2.05 002_CCZQ4 H 32.29 f N 5 8 02CQ H 32.30 g 1 407 1.89 002_CCZQ4 H 32.31 g 492 1.67 002_CCZQ4

H

WO 2011/104340 PCT/EP2011/052813 KH 32.32 h N 363 1.97 002_CCZQ4 H 32.33 h 1 407 1.96 002_CCZQ4 H 32.34 h > ~~~448 1.73 002_CCZQ4 32.35 i N 476 1.81 002_CCZQ4 H 32.36 i 1435 2.06 002_CCZQ4 32.37 i HN 391 2.08 002_CC_ZQ4 H 32.38 k 5006 1.80 002_CC_ZQ4 H 32.39 k N 64 2.78 002_CCZQ4 H 3241 514 2.71 003_CCZQ7 32.41 I N- 526 2.68 003_CCZQ7 32.42 I 540 2.81 003_CCZQ7 The acid f and H~nig's base (15pl) was dissolved in DMF (2 ml). After a few minutes TBTU (21.2 mg) was added. To this mixture was added the amin (0.07 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was purified 5 by chromatography. 112 WO 2011/104340 PCT/EP2011/052813 F F 0 N N 0 kN S N-R3 R2 The following compounds were synthesized in an analogue manner: Inter Final Reten- HPLC mediate NR2R3 Mass compound product tion time method 32.43 f 490 H 32.44 f 490 32.45 f N N- 490 5 Compound 33 4-(2-((1-(Cyanomethyl)cyclopropvl)methoxv)pyridin-3-vlamino)-N-(3 (dimethylamino)propvl)-5-methylthieno[2,3-dlpyrimidine-6-carboxamide hydrochloride 33. 1 Methyl 4-(2-((1-(cyanomethyl)cyclopropvl)methoxv)pyridin-3-vlamino)-5 10 methylthieno[2,3-dpyrimidine-6-carboxylate NH N 0 NH N S 0 113 WO 2011/104340 PCT/EP2011/052813 Prepared analogously to example 32.1 using 2-(1-((3-aminopyridin-2 yloxy)methyl)cyclopropyl)acetonitrile (264 mg) and chloro-5-methyl-thieno[2,3 d]pyrimidine-6-carboxylic acid methyl ester (152 mg). Retention time HPLC: 2.13 min 5 HPLC method: 007_CCZQ5 33. 2 4-(2-((1-(Cyanomethyl)cyclopropvl)methoxv)pyridin-3-vlamino)-5 methylthieno[2,3-dlpyrimidine-6-carboxylic acid N N 0 NH N 0 N S OH 10 Prepared analogously to example 32 Step 2 using methyl 4-(2-((1-(cyanomethyl) cyclopropyl)methoxy)pyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimid ine-6 carboxylate Yield: 85mg Retention time HPLC: 2.23 min 15 HPLC method: 003_CCZQ6 33.3 4-(2-((1-(Cyanomethyl)cyclopropvl)methoxv)pyridin-3-vlamino)-N-(3 (d imethylamino)propvl)-5-methyl-thieno[2,3-dlpyrimidine-6-carboxamide hydrochloride N N 0 NH N N H

N

20 114 WO 2011/104340 PCT/EP2011/052813 Prepared analogously to example 32.3 using 4-(2-((1-(cyanomethyl)cyclopropyl) methoxy)pyridin-3-ylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (42,5 mg) and N,N-dimethyl-1,3-propanediamine (17 mg). Yield: 42.7 mg 5 ESI mass spectrum: m/z = 480 (M+H)* Retention time HPLC: 1.69 min HPLC method: 004_CCZQ6 Compound 33.4: 10 Prepared analogously to example 32.3 using 4-(2-((1-(cyanomethyl)cyclopropyl) methoxy)pyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia. Retention Structure Name Yield Mass HPLC method time N 4-(2-((1 -(cyano methyl)cyclo N ~propyl)methoxy) pyridin-3- 18.5 004_CCZ ylamino)-5- 395 2.00 NH methylthieno[2,3 mg Q6 N O -d]pyrimidine-6 carboxamide NS NH 2 15 Compound 34 4-(2-((2,2-Difluorocyclopropyl)methoxv)pyridin-3-vlamino)-N-(3 (dimethylamino)propvl)-5-methylthieno[2,3-dlpyrimidine-6-carboxamide hydrochloride 34. 1 Methyl 4-(2-((2,2-difluorocyclopropvl)methoxv)pyridin-3-vlamino)-5 20 methylth ieno[2,3-dlipyrim id ine-6-carboxyl ate FEF N 0 NH N 0 N S OH 115 WO 2011/104340 PCT/EP2011/052813 Prepared analogously to example 32.1 using 2-((2,2 Difluorocyclopropyl)methoxy)pyridin-3-amine (200 mg) and chloro-5-methyl thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (194 mg). Yield: 57 mg 5 Retention time HPLC: 2.49 min HPLC method: 004_CCZQ6 34. 2 4-(2-((2,2-Difluorocycloproipl)methoxv)ipridin-3-vlamino)-5-methyl-thieno[2,3 dlpyrimidine-6-carboxylic acid FF N 0 NH 0 10 N S OH Prepared analogously to example 32 Step 2 using methyl 4-(2-((2,2-difluoro cyclopropyl)methoxy)pyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimid ine-6 carboxylate (56 mg) Yield: 110mg 15 Retention time HPLC: 2.37 min HPLC method: 004_CCZQ6 34. 3 4-(2-((2,2-Difluorocyclopropyl)methoxv)ipridin-3-vlamino)-N-(3 20 (dimethylamino)proipvl)-5-methyl-thieno[2,3-dlpyrimidine-6-carboxamide hydrochloride 116 WO 2011/104340 PCT/EP2011/052813 F F N 0 NH CIH N H

N

Prepared analogously to example 32.3 from 4-(2-(2,2)difluorocyclopropyl) methoxy)pyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid (27 mg) and N,N-dimethyl-1,3-propanediamine (11 mg). 5 Yield: 8.6 mg ESI mass spectrum: m/z = 477 (M+H)* Retention time HPLC: 1.83min HPLC method: 004_CCZQ6 10 Compound 34.4: Prepared analogously to example 32.3 using 4-(2-((2,2 d ifl uorocyclopropyl)methoxy)pyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimid ine-6 carboxylic acid Retention Structure Name Yield Mass HPLC method time 4-(2-((2,2 difluorocyclopro N O pyl)m ethoxy)- 004_CCZ pyridin-3- 4 mg 392 2.19 NH ylamino)-5- Q6 methylthieno[2,3 N O -d]pyrimidine-6 N S

NH

2 carboxamide 15 Compound 35 4-(2-Isopropoxvpyridin-3-vlamino)-5-methylthieno[2,3-dlpvrimidine-6-carboxvamide 117 WO 2011/104340 PCT/EP2011/052813 35.1 Methyl 4-(2-isopropoxvipyridin-3-vlamino)-5-methyl-thieno[2,3-dlpyrimidine-6 carboxylate N 0 N N s O 5 2-Isopropoxypyridin-3-amine (1.3 g) was added to a solution of 4-Chloro-5-methyl thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (2.3 g), Xantphos (995.2 mg) and Cesium carbonate (3.9 g) in degassed dioxane (40 ml). The mixture was again degassed in a sonicator for 15 min before addition of Pd 2 (dba) 3 . The reaction mixture was then heated under a nitrogen atmosphere to 900C for 3h. The mixture was 10 cooled, filtered and the solid washed with dioxane. The residues were combined and poured into an ammonium hydroxide solution. The solid was filtered off to yield the desired product. Yield: 2.05 g 15 35.2 4-(2-Isopropoxvipyridin-3-vlamino)-5-methyl-thieno[2,3-dlpyrimidine-6 carboxylic acid N 0 N N0 kN S 0 Methyl 4-(2-isopropoxypyridin-3-ylamino)-5-methyl-thieno[2,3-d]pyrimidine-6 carboxylate (2.04 g) was dissolved in methanol (24.0 ml), NaOH (2M; 6.0 ml) was 20 added and the mixture was stirred at 600C for 1h. Then the reaction was cooled and washed with dichloromethane. The aqueous layer was acidified to pH 5 with conc. HCI and the precipitate was filtered and washed with water. Yield: 1.5 g ESI mass spectrum: m/z = 345 (M+H)' 25 118 WO 2011/104340 PCT/EP2011/052813 35.3 4-(2-Isopropoxvpyridin-3-vlamino)-5-methyl-thieno[2,3-d1pyrimidine-6 carboxamide Y N 0 N N 0 N~N kN S N 5 HATU (182.0 mg) was added to an ice cooled solution of 150 mg 4-(2 Isopropoxypyridin-3-ylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and DIPEA (83.0 pl) in DMF (3.0 ml). The mixture was stirred at 00C for 20 min then ammonia/ MeOH (7M;1.5 ml) was added and it was allowed to warm to room temperature overnight. The mixture was diluted with EtOAc and washed with water, 10 2M NaOH and concentrated in vacuo. The residue was triturated with Et 2 O and filtered to give the title compound. Yield: 90.0 mg ESI mass spectrum: m/z = 344 (M+H)* 15 Compound 36 N-(3-(Dimethylam ino)propyl)-4-(2-isopropoxvpyrid in-3-vlam ino)-5-methyl-th ieno[2,3 dIpyrimid ine-6-carboxamide N 0 N N NN kN S 0 Prepared analogously to example 1.3 using 4-(2-isopropoxypyridin-3-ylamino)-5 20 methylthieno[2,3-d]pyrimidine-6-carboxylic acid (descirbed in 1.2) and 3 dimethylaminopropylamine. The resultant product was purified by chromatography. Yield: 68 mg ESI mass spectrum: m/z = 427 (M-H) 25 119 WO 2011/104340 PCT/EP2011/052813 Further analogues of 36 The compounds listed in the following table were synthesized analogously to example 1.3 using 4-(2-isopropoxypyridin-3-ylamino)-5-methylthieno[2,3 d]pyrimidine-6-carboxylic acid and the corresponding amine 5 Table 1: Reten- HPLC Structure Name Yield Mass tion time method 36.1 N 4-(2- CSFTF Isopropoxypyridin N 3-ylamino)-5- AMeOH N S N methyl-N-(3- 15 455 1.52 (pyrrolidin-1- mg P30V#00 N yI)propyl)thieno[2,3 d]pyrimidine-6- 01 carboxamide 36.2 N N-(4-Hydroxybutyl) isopropoxypyridin 3-ylamino)-5- 11.4 N S N 416 1.92 { methylthieno[2,3- mg d]pyrimidine-6 carboxamide 0 36.3 N-Ethyl-4-(2 N 0 isopropoxypyridin N 3-ylamino-5- 14.8 N methylthieno[2,3- 372 1.99 N S N d]pyrimidine-6 carboxamide 36.4 N O 4-(2 Isopropoxypyridin N N 0 3-ylamino)-5 methyl-N- 24.8 N471 1.49 morpholinopropyl)th mg ieno[2,3 SN d]pyrimidine-6 0 carboxamide 120 WO 2011/104340 PCT/EP2011/052813 36.5 4-(2 Isopropoxypyridin N O 3-ylamino)-5 N methyl-N N (morpholin- 31. 433 1.5 N S N 2ylmethyl) mg thieno[2,3 d]pyrimidine-6 carboxamide 36.6 N-((1S,2S)-2 Aminocyclopropyl) N 0 N isopropoxypyridin N 3-ylamino)-5- 399 1.5 N S N methylthieno[2,3- mg N d]pyrimidine-6 carboxamide 36.7 4-(2 Isopropoxypyridin N0 3ylam i no)-5-m ethyl o N-(2 22.1 N (methylamino)-2- 415 1.87 N S N oxoethyl)thieno[2,3- mg N d]pyrimidine-6 0 carboxamide 36.8 N 0 N Isopropoxypyridin N o 3ylamino)-5-methyl- 16.4 N S N N-(oxazol-5- mg 0 ylmethyl)thieno[2,3 d]pyrimidine-6 121 WO 2011/104340 PCT/EP2011/052813 carboxamide 36.9 4-(2 N 0o Isopropoxypyridin N 3ylam i no)-5-m ethyl N N-(2-(piperidin-1- 16.4 N S N 455 1.53 yl)ethyl)thieno[2,3- mg N d]pyrimidine-6 carboxamide 36.10 4-(2 N 0 Isopropoxypyridin 3ylam i no)-5-m ethyl N N 30.9 methylpiperidin-4- 441 1.5 N S N yl)thieno[2,3- mg N d]pyrimidine-6 carboxamide 36.11 N-(3 N O Hydroxypropyl)-4 N (2 N N isopropoxypyridin- 13.7 3ylamino)-5- 402 1.9 N S N methylthieno[2,3- mg d]pyrimidine-6 0 carboxamide 36.12 N-(2-Hydroxyethyl) N O 4-(2 N isopropoxypyridin N 3ylamino)-5 9 mg 388 1.87 N s N methylthieno[2,3 d]pyrimidine-6 0 carboxamide 122 WO 2011/104340 PCT/EP2011/052813 36.13 N-(2 Hydroxypropyl)-4 N0 o (2 N isopropoxypyridin N 0 1. 3ylamino)-5- 402 1.92 N S N methylthieno[2,3- mg 0 d]pyrimidine-6 carboxamide 36.14 4-(2 N O Isopropoxypyridin 3ylam i no)-5-m ethyl ClN o N-(morpholin-3 N 28.1 ylmethyl) 443 1.51 thieno[2,3 N d]pyrimidine-6 carboxamide 36.15 4-(2 Isopropoxypyridin 3ylam i no)-5-m ethyl N N-((1-methyl-1H N- imidazol-4- 28.3 N S N 438 1,5 yl)m ethyl mg N )thieno[2,3 N d]pyrimidine-6 carboxamide 36.16 N-(4 N 0 (Dimethylamino) N but-2-ynyl)-4-(2 N isopropoxypyridin- 29.6 N S N 3-ylamino)-5- 439 1.5 methylthieno[]2,3- mg d]pyrimidine-6 N carboxamide 123 WO 2011/104340 PCT/EP2011/052813 36.17 N-((trans)-4 N O Hydroxycyclohexyl) N -4-(2-isopropoxy N pyridin-3-ylamino)- 17.7 442 1.94 N S N 5-methylthieno[2,3- mg d]pyrimidine-6 0 carboxyamide 36.18 N-(Cyanomethyl)-4 (2-isopropoxy N N pyridin-3-ylamino)- 19.1 5-methylthieno[2,3- 383 1.93 N S N d]pyrimidine-6- mg \ carboxyamide 36.19 N N-(4-Aminobut-2 O-r ynyl )-4-(2 N isopropoxypyridin N 0 3-ylamino)-5- 23.4 N S N411 1.51 methylthieno[2,3- mg d]pyrimidine-6 N carboxyamide Compound 37 4-(4-Fluoro-2-isopropoxvphenylamino)-5-methyl-thieno[2,3-dlpyrimidine-6-carboxylic acid 5 37.1 Methyl 4-(4-fluoro-2-isopropoxvphenylamino)-5-methyl-thieno[2,3-dlpyrimidine 6-carboxylate F 0 N s 0 N S 0 4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (112 mg), 4 10 fluoro-2-isopropoxyaniline (77.9 mg) and p-toluenesulfonic acid monohydrate (15 mg) 124 WO 2011/104340 PCT/EP2011/052813 were dissolved in dioxane (3.0 ml). The reaction was heated at 110 C under microwave irradiation. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane and extracted with water. The organic phase was dried and concentrated in vacuo. The residue was triturated with 5 diisopropyl ether and filtered. Yield: 106 mg ESI mass spectrum: m/z = 376 (M+H)* Retention time HPLC: 4.22 min HPLC method: AC 1 10 37.2 4-(4-Fluoro-2-isopropoxvphenvlamino)-5-methyl-thieno[2,3-dlpvrimidine-6 carboxylic acid F O N0 kN S 0 15 Methyl 4-(4-fluoro-2-isopropoxyphenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6 carboxylate (451 mg) and lithium hydroxide (865 mg) was dissolved in a mixture of THF: methanol: water (1:1:1; 100ml) and was stirred at room temperatruer overnight. Then the mixture was acidified with conc. HCl, the resultant precipitate was filtered, dried and triturated with diisopropyl ether to afford the title compound. 20 Yield: 378 mg ESI mass spectrum: m/z = 362 (M+H)* Retention time HPLC: 2.72 min HPLC method: AC 1 25 Compound 38 4-(4-Fluoro-2-isopropoxvphenvlamino)-5-methyl-thieno[2,3-dlpvrimidine-6-carboxylic acid 125 WO 2011/104340 PCT/EP2011/052813 F 0 N )N N N k N S 0 Prepared analogously to example 35.3 using 4-(4-Fluoro-2isopropoxyphenylamino) 5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (descirbed in 37.2) and N,N-Dimetyhl-1,3-propanediamine. 5 Yield: 355 mg ESI mass spectrum: m/z = 446 (M+H)* Retention time HPLC: 2.72 min HPLC method: WOOl_001 10 Compound 39 4-[2-(1 -Ethvlcarbamovl-ethoxv)-4-fluoro-phenvlaminol-5-methyl-thieno[2,3-d pyrimidine-6-carboxylic acid N 0 FO F 0 N N ~ 0 kN S 0 To the intermediate XVIII (0.36 g) in THF:methanol 1:1 (20 ml) was added sodium 15 hydroxide 1 M (2.00 ml) and stirred at 500C overnight. Then the mixture was acidified by addition of hydrochloric acid and concentrated. The residue was diluted with water, filtrated and the solid was washed with diethylether. Yield: 0.30 g ESI mass spectrum: m/z = 419 (M+H)* 20 Retention time HPLC: 2.65 min HPLC method: A_ 4 Compound 40 126 WO 2011/104340 PCT/EP2011/052813 4-[2-(1 -Ethvlcarbamovl-ethoxv)-4-fluoro-phenvlaminol-5-methyl-thieno[2,3-d pyrimidine-6-carboxylic acid (3-dimethylamino-proipvl)-amide N 0.I F 0 N N 0 / N Prepared analogously to example 5 using 4-[2-(1 -ethylcarbamoyl-ethoxy)-4-fluoro 5 phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (60 mg) and N,N dimethyl-1,3-propanediamine (24 pl). Yield: 0.32 g ESI mass spectrum: m/z = 503 (M+H)* Retention time HPLC: 1.97 min 10 HPLC method: A_ 4 Compound 41 The compound listed in the following table was synthesized analogously to example 40 using 4-[2-(1 -ethylcarbamoyl-ethoxy)-4-fluoro-phenylamino]-5-methyl-thieno 15 [2,3-d]pyrimidine-6-carboxylic acid (compound 39) and ethanolamine. Retention Structure Name Yield Mass HPLC method time 4-[2-(1 N Ethylcarbamoyl ethoxy)-4-fluoro F O phenylamino]-5 methyl- 25 mg 462 2.33 A 4 N thieno[2,3 o d]pyrimidine-6 N carboxylic N S N-- acid(2-hydroxy 0 ethyl)-amide Compound 42 4-[2-(3-Amino-1 -methyl-propoxv)-ipridin-3-vlaminol-5-methyl thieno[2,3-dl pyrimidine-6-carboxylic acid (2-hydroxv-ethyl)-amide 127 WO 2011/104340 PCT/EP2011/052813 N N 0 N N 0 42.1 4-[2-(3-tert-Butoxvcarbonylamiino-1 -methyl-propoxv)-pvridin-3-vlamino 5-methyl-thieno[2,3-dl pyrimidine-6-carboxylic acid o O N 0 N N -- 0 5 kN S 0 To the product from 16.1 (0.20 g) in DMF (5 ml) was added CDI (75 mg) and stirred for 2 hours at 700C. Then 2-amino-ethanol (28,8 pl) was added and stirred at rt overnight. The reaction mixture was concentrated. Purification was achieved by chromatography. 10 Yield: 0.16 g ESI mass spectrum: m/z = 417 (M+H)* Retention time HPLC: 2.18 min HPLC method: A_ 10 15 Compound 43 4-[2-(3-Methanesulfonylamino-1-methyl-propoxv)-ipridin-3-vlaminol-5-methyl thieno[2,3-dl pyrimidine-6-carboxylic acid (2-hydroxv-ethyl)-amide 128 WO 2011/104340 PCT/EP2011/052813 / I N N 0 N N 0 N S N--\ Methanesulfonyl chloride (19 pl) was added to a mixture of the product from example 42 (0.11 g), DCM (5 ml) and DBU (75 pl). The mixture was stirred at rt overnight. The reaction mixture was concentrated and then purified by chromatography. 5 Yield: 9.8 mg ESI mass spectrum: m/z = 495 (M+H)* Retention time HPLC: 2.38 min HPLC method: AC 1 10 Compound 44 4-[2-(3-Methanesulfonylamino-1-methyl-propoxy)-ipridin-3-vlaminol-5-methyl thieno[2,3-dl pyrimidine-6-carboxylic acid / I N N 0 N N 0 N S 0 44.1 4-[2-(3-Methanesulfonylamino-1-methyl-propoxv)-pvridin-3-vlaminol-5 15 methyl-thieno[2,3-dl pyrimidine-6-carboxylic acid methyl ester 129 WO 2011/104340 PCT/EP2011/052813 N N 0 N N 0 N S /0 Prepared analogously to example 43 using the product from 15.2. Yield: 330.0 mg ESI mass spectrum: m/z = 466 (M+H)* 5 44.2 4-[2-(3-Methanesulfonylamino-1-methyl-propoxv)-ipridin-3-vlaminol-5 methyl-thieno[2,3-dl pyrimidine-6-carboxylic acid N N O /1 N N 0 N S 0 Sodium hydroxid 1 M (3 ml) was added to a mixture of the product from example 44.1 10 (0.27 g) and MeOH (5 ml). The mixture was stirred at 500C for 1 hour. Then the reaction mixture was neutralized with hydrochloric acid 1 M (3 ml) and concentrated. The residue was diluted with water and extracted with DCM. The organic layer was washed with a sodium chloride solution, dried and concentrated. Yield: 210.0 mg 15 ESI mass spectrum: m/z = 452 (M+H)* Retention time HPLC: 1.62 min HPLC method: A_ 10 Compound 45 20 4-[2-(3-Methanesulfonylamino-1-methyl-propoxv)-ipridin-3-vlaminol-5-methyl thieno[2,3-dl pyrimidine-6-carboxylic acid amide 130 WO 2011/104340 PCT/EP2011/052813 / I N N 0 N 0 NN N S N A reaction mixture of the product from example 44.2 (50 mg), TBTU (36 mg), DIPEA (39 pl), ammonia 0.5M in THF (222 pl), THF (3 ml) was stirred at rt for 1 hour. Then the mixture was concentrated and then purified by chromatography. 5 Yield: 18.0 mg ESI mass spectrum: m/z = 451 (M+H)* Retention time HPLC: 1.46 min HPLC method: A_ 10 10 Compound 46 4-[2-(3-Methanesulfonylamino-1-methyl-propoxv)-ipridin-3-vlaminol-5-methyl thieno[2,3-dl pyrimidine-6-carboxylic acid (3-dimethylamino-proplv)-amide / I N N 0 N N N

/N

Prepared analogously to example 45 using the product from 44.2. 15 Yield: 62.0 mg ESI mass spectrum: m/z = 536 (M+H)* Retention time HPLC: 1.14 min HPLC method: A_ 10 20 Compound 47 131 WO 2011/104340 PCT/EP2011/052813 4-[2-(3-Methanesulfonylamino-1 -methyl-propoxv)-pvridin-3-vlaminol-5-methyl thieno[2,3-dl pyrimidine-6-carboxylic acid (3-dimethylamino-propvl)-amide F F 0 N 0 N I N S 0 4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (0.2 g), _4 5 amino-3-(2-fluoro-1-fluoromethyl-ethoxy)-benzonitrile (0.17 g), p-toluenesulfonic acid monohydrate (0.16 g) and isopropanol (3.0 ml) were stirred at 900C for 2 hours. Then the mixture was poured in water and filtrated.The solid was washed with water and dried in an oven at 700C. Yield: 160.0 mg 10 ESI mass spectrum: m/z = 419 (M+H)* Retention time HPLC: 2.05 min HPLC method: AC 1 Compound 48 15 4-[4-Cyano-2-(2-fluoro-1 -fluoromethyl-ethoxv)-phenvlaminol-5-methyl thieno[2,3-dl pyrimidine-6-carboxylic acid (3-iprrolidin-1-vl-propvl)-amide F F 0 N N N 48.1 4-[4-Cvano-2-(2-fluoro-1 -fluoromethyl-ethoxv)-phenvlaminol-5-methyl thieno[2,3-dl pyrimidine-6-carboxylic acid 20 132 WO 2011/104340 PCT/EP2011/052813 F F 0 N 0 N I kN S 0 The product from example 47 (1.4 g) was dissolved in THF (200 ml). 10 ml water and LiOH (0.48 g) were added. The mixture was stirred at rt for 4 days. Then the mixture was acidified with 10 % citric acid and concentrated. The residue was dried in an 5 oven at 700C. Yield: 950.0 mg 48.2 4-[4-Cvano-2-(2-fluoro-1 -fluoromethyl-ethoxv)-phenvlaminol-5-methyl thieno[2,3-dl pyrimidine-6-carboxylic acid (3-iprrolidin-1-vl-propvl)-amide F F 0 N 10 4-[4-Cyano-2-(2-fluoro-1 -fluoromethyl-ethoxy)-phenylamino]-5-methyl thieno[2,3-d] pyrimidine-6-carboxylic acid (100 mg), HATU (114 mg) and TEA (52 pl) were dissolved in DMF (4 ml). N,N-dimethyl-1,3-propanediamine (31 pl) was added. The mixture was stirred for 1 hour at rt. Then the mixture was poured 15 in water and filtrated.The solid was washed with water and dried in an oven at 700C. Yield: 75.0 mg ESI mass spectrum: m/z = 515 (M+H)* Retention time HPLC: 1.95 min HPLC method: AC 1 20 The following compounds were prepared analogously to example 48.2 using 4-[4 cyano-2-(2-fluoro-1 -fluoromethyl-ethoxy)-phenylamino]-5-methyl-thieno[2,3-d] 133 WO 2011/104340 PCT/EP2011/052813 pyrimidine-6-carboxylic acid and the corresponding amine. Reten HPLC Structure Name Yield Mass tion Amine method time 49 4-(4-Cyano-2-(2 fluoro-1 F F fluoromethyl N O ethoxy)- N N phenylamino]-5- 30 7489 1.9 AC 1 N methyl-thieno[2,3- mg N S N d]pyrimidine-6 N- carboxylic acid (3 dimethylamino propyl)-amide 50 4-(4-Cyano-2-(2 fluoro-1 F F fluoromethyl N O ethoxy)- N 40 N phenylamino]-5- 501 1.95 AC 1 N N o methyl-thieno[2,3- Mg N S N N d]pyrimidine-6 carboxylic acid (1 methyl-piperidin 4-yl)-amide 51 4-(4-Cyano-2-(2 fluoro-1 F F fluoromethyl N O ethoxy)- N N phenylamino]-5- 448 2.21 AC 1 N 0 methyl-thieno[2,3- M9 0 N S N O d]pyrimidine-6 carboxylic acid (2 hydroxy-ethyl) amide 134 WO 2011/104340 PCT/EP2011/052813 52 4-(4-Cyano-2-(2 fluoro-1 F F fluoromethyl ethoxy)- 50N -N phenylamino]-5- 499 1.87 AC 1 N methyl-thieno[2,3- Mg N S N- d]pyrimidine-6- N carboxylic acid (4 dimethylamino but-2-ynyl)-amide 53 4-(4-Cyano-2-(2 fluoro-1 F F fluoromethyl N ethoxy)- N 1 phenylamino]-5- 443 1.99 AC 1 N N I O N methyl-thieno[2,3- 9g N N S N- d]pyrimidine-6 carboxylic acid cyanomethyl amide Compound 54 4-[2-Cvano-methyl-methoxv)-4-fluoro-phenvlaminol-5-methyl-thieno[2,3-dlpvrimidine 6-carboxylic acid amide N F 0 N 5 kN S N 54.1 4-(4-Fluoro-2-hydroxv-phenvlamino)-5-methyl-thieno[2,3-dlpvrimidine 6-carboxylic acid F 0 N N 0 kN S 0 135 WO 2011/104340 PCT/EP2011/052813 Methyl 4-(4-fluoro-2-hydroxyphenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6 carboxylate (Intermediate Ill) (1.0 g), sodium hydroxide 1 M (10 ml), methanol (20 ml) and THF (20 ml) were stirred at rt overnight. The mixture was concentrated and diluted with EE and water. The aqueous layer was acidified with hydrochloric acid 5 and filtrated. Yield: 800 mg ESI mass spectrum: m/z = 320 (M+H)* Retention time HPLC: 2.22 min HPLC method: 004_CCZQ6 10 54.2 4-(4-Fluoro-2-hydroxv-phenvlamino)-5-methyl-thieno[2,3-dlpvrimidine 6-carboxylic acid amide F 0 N N 0 kN S N Prepared analogously to example 21.3 using the product from 66.1 15 Yield: 30 mg ESI mass spectrum: m/z = 319 (M+H)* Retention time HPLC: 1.9 min HPLC method: 004_CCZQ6 20 54.3 4-[2-Cvano-methyl-methoxv)-4-fluoro-phenvlaminol-5-methyl-thieno[2,3 dlpyrimidine-6-carboxylic acid amide N F 0 N kN S N The product from 54.2 (30 mg), 2-bromopropionitrile (13 mg), cesium carbonate (40 mg) inDMF (1 ml) were stirred at rt overnight. The mixture was 25 filtrated and the solid was washed with DMF. Water was added to the filtrate. The solid was isolated by filtration. The combined solids were freeze-dried. 136 WO 2011/104340 PCT/EP2011/052813 Yield: 14 mg ESI mass spectrum: m/z = 372 (M+H)* Retention time HPLC: 1.92 min HPLC method: 004_CCZQ6 5 Compound 55 4-[2-(1 -Carboxy-ethoxy)-4-fluoro-phenylaminol-5-methyl-thieno[2,3-dl pyrimidine-6-carboxylic acid methyl ester 0 0-5 F 0 N N 0 N S 0 10 55.1 4-[2-(1 -tert-Butoxvcarbonyl-ethoxy)-4-fluoro-phenylaminol-5 methyl-thieno[2,3-dlpyrimidine-6-carboxylic acid methyl ester 0-5 F 0 N N 0 N S 0 2-Bromopropionic acid tert-butyl-ester (1.4 g) was added to methyl 4-(4-fluoro-2 hydroxyphenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (Intermediate 15 III) (2.00 g) and cesium carbonate (4.8 g) in ACN (50 ml) and stirred at 600C for 2 hours. The mixture was diluted with water, filtrated and washed with water. Yield: 2.1 g ESI mass spectrum: m/z = 462 (M+H)* Retention time HPLC: 2.12 min 20 HPLC method: A_ 9 55.2 4-[2-(1 -Carboxy-ethoxy)-4-fluoro-phenylaminol-5 methyl-thieno[2,3-dlpyrimidine-6-carboxylic acid methyl ester 137 WO 2011/104340 PCT/EP2011/052813 0 0-5 FO F 1 N N 0 N S 0 A mixture of the product from 55.1 (2.1 g) and 50% trifluoroacetic acid in DCM was stirred at rt overnight. Then the mixture was concentrated and the residue was triturated with diethylether. 5 Yield: 1.9 g ESI mass spectrum: m/z = 406 (M+H)* Retention time HPLC: 1.96 min HPLC method: A_ 9 10 Comound 56 4-{2-[1-(3-Amino-proipvIcarbamoyl)-ethoxyl-4-fluoro-phenylamino}-5-methyl thieno[2,3-dlpyrimidine-6-carboxylic acid methyl ester N N 0 F 0 N N 0 N S 0 56.1 4-{2-[1-(3-tert-Butoxvcarbonylamino-proiplcarbamoyl)-ethoxyl-4-fluoro 15 phenylamino}-5-methyl-thieno[2,3-dlpyrimidine-6-carboxylic acid methyl ester 138 WO 2011/104340 PCT/EP2011/052813 O N N 0-I F 0 N N -- 0 kN" S 0 The product from 55 (170 mg) and TBTU (150 mg) was dissolved in ACN (5 ml). TEA (150 pl) was added to the mixture. The mixture was stirred for 15 min. at rt. Then tert-butyl N-(3-Aminopropyl)carbamate (200 mg) was added. The mixture 5 was stirred at 500C for 2 days. Afterwards the mixture was diluted with water and filtrated. The solid was washed with water and dried in an oven Yield: 176 mg ESI mass spectrum: m/z = 562 (M+H)* Retention time HPLC: 2.21 min 10 HPLC method: A_ 9 56.2 4-{2-[1-(3-Amino-proipvlcarbamoyl)-ethoxyl-4-fluoro phenylamino}-5-methyl-thieno[2,3-dlpyrimidine-6-carboxylic acid methyl ester N N 0-I F 0 N N S 0 15 A mixture of the product from 56.1 (30 mg) and 25% trifluoroacetic acid in DCM (2 ml) was stirred at rt for 4 hours. The mixture was concentrated. Yield: 25 mg ESI mass spectrum: m/z = 462 (M+H)* 139 WO 2011/104340 PCT/EP2011/052813 Retention time HPLC: 1.96 min HPLC method: A_ 9 Comound 57 5 4-{2-[1-(3-Amino-proipvlcarbamovl)-ethoxyl-4-fluoro-phenvlamino}-5-methyl-thieno [2,3-dlpvrimidine-6-carboxylic acid (2-hydroxv-ethyl)-amide N N F 0 N N -\ ,-0 57.1 4-{2-[1-(3-tert-Butoxvcarbonylamino-propvlcarbamovl)-ethoxyl-4-fluoro phenvlamino}-5-methyl-thieno[2,3-dlpvrimidine-6-carboxylic acid O N N 051 F 0 N 1 0 10 N S 0 To the product from 55 (130 mg) in THF:MeOH=1:1 (5 ml) was added sodium hydroxide solution 1 M (580 pl) and stirred at 400C overnight. The mixture was cooled down to rt and added Hydrochloric acid 1 M (580 ml). Then the methanol was concentrated and the residue with DCM diluted. The organic layer was 15 seperated by a cartridge and concentrated. The residue was triturated with diethylether. Yield: 113 mg 140 WO 2011/104340 PCT/EP2011/052813 57.2 4-{2-[1 -(3-Amino-proipvlcarbamoyl)-ethoxyl-4-fluoro-phenylamino}-5 methyl-thieno[2,3-dlpyrimidine-6-carboxylic acid (2-hydroxy-ethyl)-amide N N F 0 N N -\ ,-0 The product from 57.1 (115 mg) and TBTU (70 mg) were dissolved in DMF 5 (1.5 ml). TEA (75 pl) was added and the mixture was stirred for 5 min. at rt. Ethanolamine (20 pl) was added and the mixture was stirred at rt overnight. Afterwards the mixture was diluted with methanol. Purification was achieved by chromatography. The combined fractions were concentrated. A mixture of DCM:TFA=50:50 was added to the residue and the mixture was stirred at rt for 1 10 hour. Then the mixture was concentrated. A solution of hydrochloric acid in methanol was added and the mixture was concentrated. Yield: 70 mg ESI mass spectrum: m/z = 491 (M+H)* Retention time HPLC: 1.92 min 15 HPLC method: A_ 9 Compound 58 4-{2-[1-(2-Amino-ethylcarbamoyl)-ethoxyl-4-fluoro phenylamino}-5-methyl-thieno[2,3-dlpyrimidine-6-carboxylic acid methyl ester N N F 0 N 20 141 WO 2011/104340 PCT/EP2011/052813 58.1 4-{2-[1 -(2-tert-Butoxvcarbonylam ino-ethylcarbamoyl)-ethoxyl-4-fl uoro phenylamino}-5-methyl-thieno[2,3-dlpyrimidine-6-carboxylic acid methyl ester O N N 0-I F 0 N N -- 0 kN" S 0 5 Prepared analogously to example 56.1 using the product from 55 (170 mg) and tert butyl N-(2-aminoethyl)carbamate (90 pl). Yield: 135 mg ESI mass spectrum: m/z = 548 (M+H)* 10 58.2 4-{2-[1-(2-Amino-ethylcarbamoyl)-ethoxyl-4-fluoro-phenylamino}-5-methy thieno[2,3-dlpyrimidine-6-carboxylic acid methyl ester N N 0-I F 0 N N 0 N S /0 Prepared analogously to example 56.2 using the product from 57.3 (170 mg). Yield: 28 mg 15 ESI mass spectrum: m/z = 448 (M+H)* Retention time HPLC: 1.83 min HPLC method: A_ 9 Compound 59 142 WO 2011/104340 PCT/EP2011/052813 4-{2-[1 -(2-Amino-ethylcarbamovl)-ethoxyl-4-fluoro-phenvlamino}-5-methyl-thieno[2,3 dlpyrimidine-6-carboxylic acid (2-hydroxy-ethyl)amide N N F 0 k N - \ , o 59.1 4-{2-[1-(2-tert-Butoxvcarbonylamino-ethylcarbamoyl)-ethoxyl-4-fluoro 5 phenvlamino}-5-methyl-thieno[2,3-dlpvrimidine-6-carboxylic acid 051 O N N F 0 Prepared analogously to example 57.1 using the product from 58 (90 mg) . Yield: 73 mg ESI mass spectrum: m/z = 534 (M+H) 10 59.2 [2-(2-{5-Fluoro-2-[6-(-hydroxv-etvhlcabamovl) -5 methyl-thieno[2,3-dospyrimidtoxme5.uintol-hphenoxv}-ropion0laminol ethyll-carbamic acid tet-butyl ester 143 WO 2011/104340 PCT/EP2011/052813 0 O N N F 0 N N kN S N-\o The product from 59.1 (73 mg) and TBTU (48 mg) were dissolved in DMF (1 ml). TEA (48 pl) was added and the mixture was stirred for 5 min. at rt before ethanolamine (11 pl) was added. The mixture was stirred at rt overnight. The mixture 5 was then diluted with methanol. Purification was achieved by chromatography. Yield: 40 mg ESI mass spectrum: m/z = 577 (M+H)* Retention time HPLC: 1.56 min HPLC method: A_ 9 10 59.3 4-{2-[1-(2-Amino-ethvlcarbamovl)-ethoxyl-4-fluoro-phenvlamino}-5 methyl-thieno[2,3-dlpvrimidine-6-carboxylic acid (2-hydroxy-ethyl)amide N N F 0 k N - \ , o A mixture of the product from 59.2 (40 mg) and 25% trifluoroacetic acid in 15 DCM (5 ml) was stirred at rt for 4 hours. Methanol and a solution of hydrochloric acid in methanol were added. Then the mixture was concentrated. Yield: 7 mg ESI mass spectrum: m/z = 462 (M+H)* Retention time HPLC: 1.96 min 144 WO 2011/104340 PCT/EP2011/052813 HPLC method: A_ 9 Compound 60 4-[4-Fluoro-2-(2-hydroxy-1,2-dimethyl-propoxy)-phenylamino]-5-methyl-thieno[2,3 5 d]pyrimidine-6-carboxylic acid amide F 0 4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid amide (intermediate XXIV) (100 mg), intermediate XXVI (120 mg) and p-toluenesulfonic acid (5 mg) in dioxane (2 ml) were stirred at 100 C for 6 hours. Then the mixture was filtrated. The 10 solid was washed with methanol. Yield: 145 mg ESI mass spectrum: m/z = 405 (M+H)* Retention time HPLC: 1.245 min HPLC method: M2-SB-C18 15 Compound 61 4-[2-(1 -Ethylcarbamoyl-ethoxy)-4-fluoro-phenylamino}-5-methylthieno[2,3dlpyrimidine -6-carboxylic acid methyl ester N 0-5 F 0 N N 0 N S /0 20 The product from 55 (500 mg) and TBTU (400 mg) were dissolved in ACN (10 ml). TEA (430 pl) was added and the mixture was stirred for 20 min. at rt before Ethylamine (1.5 ml) was added. The mixture was stirred at rt overnight. Then the mixture was diluted with methanol. Purification was achieved by chromatography. 145 WO 2011/104340 PCT/EP2011/052813 Yield: 360 mg ESI mass spectrum: m/z = 433 (M+H)* Retention time HPLC: 1.89 min HPLC method: A_ 9 5 The following compound was prepared analogously to example 61 using the product from 55 and the corresponding amine. Reten HPLC Structure Name Yield Mass tion Amine method time 62 4-{2-[1-(2 Dimethylamino ethylcabamoyl) N ethoxy]-4-fluoro 0O phenylamino}-5- 136 41 F o476 2.17 A- 4 methyl- mg N thieno[2,3 N d]pyrimidine-6 N S /0 carboxylic acid methyl ester 10 Compound 63 4-[2-Cvano-methyl-methoxv)-4-fluoro- phenvlaminol-5-methyl-thieno[2,3 dlpyrimidine-6-carboxylic acid (2-dimethylamino-proipv)-amide N F O N N 0 N S N-\ _

/N

63.1 4-(4-Fluoro-2-hydroxv-phenvlamino)-5-methyl-thieno[2,3-dlpvrimidine-6 15 carboxylic acid 146 WO 2011/104340 PCT/EP2011/052813 F 0 N 0 N I kN S 0 Intermediate 111 (333 mg), sodium hydroxide solution 1M (5 ml) in 10 ml methanol and 10 ml THF were stirred at rt overnight. Then the mixture was acidified with hydrochloric acid and filtrated. 5 Yield: 256 mg ESI mass spectrum: m/z = 320 (M+H)* Retention time HPLC: 2.22 min HPLC method: 004_CCZQ6 10 63.2 4-(4-Fluoro-2-hydroxv-phenvlamino)-5-methyl-thieno[2,3-dlpvrimidine-6 carboxylic acid (3-dimethylamino-proipvl)-amide F 0 N 0 N N S N Prepared analogously to example 21.1 using the product from 63.1 (150 mg) and N,N-dimethyl-1,3-propanediamine (90 pl). 15 Yield: 157 mg ESI mass spectrum: m/z = 404 (M+H)* Retention time HPLC: 1.62 min HPLC method: 004_CCZQ6 20 63.3 4-[2-Cyano-methyl-methoxv)-4-fluoro- phenvlaminol-5-methyl-thieno[2,3 dlpyrimidine-6-carboxylic acid (2-dimethylamino-proipv)-amide 147 WO 2011/104340 PCT/EP2011/052813 N F O N N 0 N S N /N To the product from 63.2 (157 mg) in DMF (4 ml) was added cesium carbonate (165 mg). After 5 min. 2-Bromopropionitrile (37 pl) was added and the mixture was stirred at rt overnight. Then the mixture was concentrated and diluted with DCM and water. 5 The organic layer was seperated, dried and concentrated. Yield: 130 mg ESI mass spectrum: m/z = 457 (M+H)* MN K 2 -Inhibition 10 Kinase Fluorescence Polarization Assays Assay principle: Inhibitory potency of compounds against Mnk1, Mnk2a and other kinases was assessed with assays based on a format known to those skilled in the art as the indirect (competitive) fluorescence polarization. The assay detection 15 system comprises a small fluorophore-labeled phospho-peptide (termed ligand) bound to a phospho-specific antibody. The product generated by the kinase reaction competes with the ligand for antibody binding. Based on the larger molecular volume of the bound ligand, which results in a lower rotation rate in solution, its emitted light has a higher degree of polarization than the one from the free ligand. 20 Description of the specific homogenous kinase assay Example 2a. Mnk1 and Mnk2a in vitro kinase assay As a source of enzyme, human Mnk1 and human Mnk2a were expressed as GST fusion proteins in E. coli, purified to >80% homogeneity by glutathione affinity 25 chromatography and activated in vitro with pre-activated ERK2. In brief, the open reading frames of human Mnk1 and Mnk2a were amplified from cDNA using the forward/reverse primer pairs 148 WO 2011/104340 PCT/EP2011/052813 SEQ ID NO: 1 5'TTTAGGATCCGTATCTTCTCAAAAGTTGG / SEQ ID NO: 2 5' CTGGGTCGACTCAGAGTGCTGTGGGCGG and SEQ ID NO: 3 5'ACAGGGATCCGTGCAGAAGAAACCAGCC / 5 SEQ ID NO: 4 5'GATGGTCGACTCAGGCGTGGTCTCCCACC (utilized restriction sites underlined), respectively, and cloned into the BamHI and Sall sites of the vector pGEX-4T1 (Amersham, Sweden, cat. no. 27-4580-01). These constructs allow prokaryotic expression of Mnk1 or Mnk2a as fusion protein with a 10 N-terminal glutathione S-transferase (GST) tag, referred to as GST-Mnk1 or GST Mnk2a. The following expression and purification procedure was identical for GST Mnk1 and GST-Mnk2a, referring in general to GST-Mnk, when not distinguishing between the two isoforms. Expression of GST-Mnk was in E. coli BL21 (Merck Biosciences, Germany, cat. no. 69449). Cells were grown in LB-Bouillon (Merck, 15 Germany, cat. no. 1.10285) supplemented with 100 pg/ml ampicillin (Sigma, Germany, cat. no. A9518) at 370C. When the culture had reached a density corresponding to an A 600 of 0.8, an equal volume of ice cold LB/ampicillin was added, the culture transferred to 250C and induced for 4 h with 1 mM isopropyl thiogalactoside (IPTG, Roth, Germany, cat. no. 2316.4). Cells harvested by 20 centrifugation were resuspended in 10 ml lysis buffer (50 mM tris(hydroxymethyl)aminomethane hydrochloride (Tris/HCI, Sigma, Germany, cat. no. T5941) pH 7.5, 300 mM sodium chloride (NaCI, Sigma, Germany, cat. no. S7653), 5% (w/v) glycerol (Sigma, Germany, cat. no. G5516), 3 mM DTT dithiotreitol (DTT, Sigma, Germany, cat. no. D9779)) per gram wet weight cell pellet. Lysates were 25 prepared by disruption of cells with a sonifier and subsequent clearing by centrifugation at 38000 g for 45 min at 40C. The lysate was applied to a GSTPrep FF 16/10 column (Amersham, Sweden, cat. no. 17-5234-01) equilibrated with lysis buffer. Removal of unbound material was with 30 3 column volumes (CV) lysis buffer. Elution was with 2 CV of elution buffer (50 mM Tris/HCI pH 7.5, 300 mM NaCI, 5% (w/v) glycerol, 20 mM glutathione (Sigma, Germany, cat. no. G4251)). Peak fractions were pooled and the protein transferred into storage buffer (50 mM Tris/HCI pH 7.5, 200 mM NaCI, 0.1 mM ethylene glycol 149 WO 2011/104340 PCT/EP2011/052813 bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA, Aldrich, Germany, cat. no. 23,453-2), 1 mM DTT, 10% (w/v) glycerol, 0.5 M sucrose (Sigma, Germany, cat. no. S0389) by gel filtration on a PD10 desalting column (Amersham, Sweden, cat. no. 17-0851-01). Aliquots were shock frozen in liquid nitrogen and stored at -80C. 5 Activation of Mnk1 and Mnk2a was at a concentration of 2.5 pM of either purified GST-Mnk1 or GST-Mnk2a by incubation with 150 nM pre-activated NHis-ERK2 (see ERK2 assay for preparation) and 50 pM adenosine triphosphate (ATP, Sigma, cat. no. A2699) in a buffer comprising 20 mM N-(2-hydroxyethyl) piperazine-N'-(2 10 ethanesulfonic acid) (HEPES, Fluka, Germany, cat. no 54459)/potassium hydroxide (KOH, Roth, Germany, cat. no 6751.1) pH 7.4, 10 mM magnesium chloride (MgCl 2 , Sigma, Germany, cat. no. M2670), 0.25 mM DTT, 0.05% (w/v) polyoxyethylene 20 stearylether (Brij 78, Sigma, Germany, cat. no. P4019) (HMDB buffer) for 45 min at 300C. After the incubation, the preparation was aliquoted into single-use samples, 15 shock frozen in liquid nitrogen, stored at -800C and utilized for Mnkl or Mnk2a kinase assays as detailed below. The presence of activating kinase has been tested to not interfere with the Mnk activity assay. SUBSTRATE: A carboxy-terminal amidated 12mer peptide with the sequence 20 SEQ ID NO: 5 TATKSGSTTKNR, derived from the amino acid sequence around serine 209 of the eukaryotic translation initiation factor 4E (eIF4E) has been synthesized and purified by high performance liquid chromatography (HPLC) to >95% (Thermo, Germany). The serine residue phosphorylated by Mnk kinases is underlined. 25 LIGAND: The peptide TATKSG-pS-TTKNR, containing an amidated carboxy terminus and conjugated at the amino-terminus with the oxazine derived fluorophore depicted below was synthesized and used as ligand. 150 WO 2011/104340 PCT/EP2011/052813 N N HOOC -3 ANTIBODY: SPF New Zealand White Rabbits have been immunized according to standard protocols with the peptide NH2-CTATKSG-pS-TTKNR-CONH2, coupled to 5 keyhole limpet hemocyanin (KLH). The immune globulin G (IgG) fraction was purified from serum of boosted animals by techniques known in the art. In brief, serum was subjected to protein A affinity chromatography. Eluted material was precipitated at 50% cold saturated ammonium sulfate, pellets dissolved and desalted. The resulting material was appropriate for use in below described assay without further antigen 10 specific purification. ASSAY SETUP: Inhibition of kinase activity of Mnk1 and Mnk2a was assessed with the same assay system, using pre-activated GST-Mnk1 or GST-Mnk2a, respectively. The kinase reaction contains 30 pM substrate peptide, 20 pM ATP, 60 nM ligand and 15 one of either 25 nM pre-activated Mnk1 or 2.5 nM pre-activated Mnk2a. The reaction buffer conditions are 16 mM HEPES/KOH pH 7.4, 8 mM MgCl 2 , 0.4 mM DTT, 0.08 % (w/v) bovine serum albumin (BSA, Sigma, Germany, cat. no. A3059), 0.008% (w/v) Pluronic F127 (Sigma, Germany, cat. no. P2443), 3% (v/v) DMSO (Applichem, Germany, cat. no. A3006). The kinase reaction is at 300C for 40 min. The kinase 20 reaction is terminated by addition of 0.67 reaction volumes of 1 pM antibody in 20 mM HEPES/KOH pH 7.4, 50 mM ethylenediaminetetraacetic acid, disodium salt (EDTA, Sigma, Germany, cat. no. E5134), 0.5 mM DTT, 0.05% (w/v) polyoxyethylene-sorbitan monolaureate (Tween 20, Sigma, Germany, cat. no. P7949). After 1 h equilibration time at room temperature, samples are subjected to 25 fluorescence polarization measurement. The fluorescence polarization readout was generated on an Analyst AD multimode reader (Molecular Devices, Sunnyvale, CA, USA) equipped with a DLRP650 dichroic mirror (Omega Opticals, Brattleboro, VT, USA, cat. no. XF2035), a 630AF50 band pass filter (Omega Opticals, Brattleboro, 151 WO 2011/104340 PCT/EP2011/052813 VT, USA, cat. no. XF1069) on the excitation and a 695AF55 band pass filter on the emission side (Omega Opticals, Brattleboro, VT, USA, cat. no. XF3076). The activity of Mnk proteins can be assayed also by other in vitro kinase assay 5 formats. For example, suitable kinase assays have been described in the literature in Knauf et al., Mol Cell Biol. 2001 Aug;21(16):5500-11 or in Scheper et al., Mol Cell Biol. 2001 Feb;21(3):743-54. In general, Mnk kinase assays can be performed such that a Mnk substrate such as a protein or a peptide, which may or may not include modifications as further described below, or others are phosphorylated by Mnk 10 proteins having enzymatic activity in vitro. The activity of a candidate agent can then be determined via its ability to decrease the enzymatic activity of the Mnk protein. The kinase activity may be detected by change of the chemical, physical or immunological properties of the substrate due to phosphorylation. In one example, the kinase substrate may have features, designed or endogenous, to 15 facilitate its binding or detection in order to generate a signal that is suitable for the analysis of the substrates phosphorylation status. These features may be, but are not limited to, a biotin molecule or derivative thereof, a glutathione-S-transferase moiety, a moiety of six or more consecutive histidine residues, an amino acid sequence or hapten to function as an epitope tag, a fluorochrome, an enzyme or enzyme fragment. The 20 kinase substrate may be linked to these or other features with a molecular spacer arm to avoid steric hindrance. In another example the kinase substrate may be labelled with a fluorophore. The binding of the reagent to the labelled substrate in solution may be followed by the technique of fluorescence polarization as it is described in the literature. In a variation of 25 this example, a fluorescent tracer molecule may compete with the substrate for the analyte to detect kinase activity by a technique which is know to those skilled in the art as indirect fluorescence polarization. In yet another example, radioactive gamma-ATP is used in the kinase reaction, and the effect of the test agent on the incorporation of radioactive phosphate in the test 30 substrate is determined relative to control conditions. 152 WO 2011/104340 PCT/EP2011/052813 It has been shown that the compounds of the invention exhibit low IC50 values in in vitro biological screening assays as described in example 2a for inhibition of Mnk 1 and/or Mnk 2 kinase activity. The following table contains the test results for exemplary compounds. 5 Example MNK2 IC 5 o [nM] Example MNK2 IC 5 o [nM] 1-2 52 20-2 25 1-3 342 20-3 59 1-4 294 21-2 15 1-5 459 21-3 11 2-1 70 21-4 54 2-2 41 21-5 42 2-3 50 21-6 12 2-4 23 21-7 24 3-1 41 21-8 20 3-2 204 22-3 296 3-3 18 23-1 78 3-4 261 23-2 6 3-5 443 23-3 4 4 3144 23-4 8 5 230 23-5 13 6-1 164 23-6 10 6-2 90 23-7 17 7 14 23-8 8 8-1 - 23-9 7 8-2 64 23-10 7 9-2 577 24 7 10-2 229 25 12 11-2 418 26-3 790 12 52 27-2 33 13 90 27-3 58 13-2 471 27-4 73 13-3 677 28-3 26 13-4 898 28-4 78 14 1017 28-5 93 15-2 174 29-3 86 16-2 8 29-4 288 16-3 74 30-2 20 16-4 44 30-3 18 17 - 30-4 48 18-2 691 30-5 57 19-1 1526 31-3 77 19-2 1166 31-4 19 20-1 142 31-5 11 153 WO 2011/104340 PCT/EP2011/052813 Example MNK2 IC50 [nM] Example MNK2 IC50 [nM] 31-6 13 33 47 31-7 20 33-4 16 32-1 267 34 54 32-2 19 34-4 15 32-3 - 35 12 32-4 13 36 29 32-5 8 36-1 35 32-6 23 36-2 42 32.7 5 36-3 26 32-8 - 36-4 44 32-9 13 36-5 25 32-10 18 36-6 55 32-11 14 36-7 27 32-12 12 36-8 19 32-13 - 36-9 63 32-14 65 36-10 32 32-15 78 36-11 45 32-16 66 36-12 31 32-17 16 36-13 54 32-18 30 36-14 64 32-19 23 36-15 24 32-20 19 36-16 22 32-21 8 36-17 46 32-22 36 36-18 26 32-23 26 36-19 14 32-24 25 37 4 32-25 13 38 6 32-26 7 39 19 32-27 7 40 20 32-28 3 41 31 32-29 170 42 70 32-30 56 43 62 32-31 146 44 24 32-32 27 45 20 32-33 65 46 84 32-34 69 47 125 32-35 35 48 12 32-36 25 49 8 32-37 8 50 13 32-38 26 51 10 32-39 35 52 25 32-40 13 53 7 32-41 25 54 11 32-42 12 55 5403 32-43 12 56 314 32-44 6 57 110 32-45 11 58 119 154 WO 2011/104340 PCT/EP2011/052813 Example MNK2 IC 50 [nM] 59 29 60 37 61 77 62 267 63 17 HPLC methods: 5 Method A_10 Waters ZQ 2000; Waters 1515 Pumpe; Waters PDA 996 Detektor; Waters 2747 Injektor DAD 200-420 nm 10 mobile phases: A: water with 0.10% formic acid B: acetonitrile with 0.10% formic acid time in min %A %B flow rate in ml/min 0.00 95 5 1.50 15 2.00 0 100 1.50 2.50 0 100 1.50 2.60 95 5 1.50 Stationary phase:X-terra MS C18; 4.6x3Omm*2.5pm 20 Method AC1 Waters ZQ 2000; Waters 1515 Pumpe; Waters PDA 996 Detektor; Waters 2747 Injektor DAD 210-420 nm 25 mobile phases: A: water with 0.10% formic acid B: acetonitrile with 0.10% formic acid time in min %A %B flow rate in ml/min 0.00 95 5 1.00 155 WO 2011/104340 PCT/EP2011/052813 0.10 95 5 1.00 3.10 2 98 1.00 4.50 2 98 1.00 5.00 95 5 1.00 5 Stationary phase: X-terra MS C18; 4.6x3Omm*2.5pm Method A_9 (pos/neg switch method) 10 Waters ZQ 2000; Waters 1515 Pumpe; Waters PDA 996 Detektor; Waters 2747 Injektor DAD 200-420 nm mobile phases: A: water with 0.10% formic acid 15 B: acetonitrile with 0.10% formic acid time in min %A %B flow rate in ml/min 0.00 95 5 1.50 2.00 0 100 1.50 2.50 0 100 1.50 20 2.60 95 5 1.50 Stationary phase: X-terra MS C18; 4.6x3Omm*2.5pm Method CSFTFAMeOHP30V#004_CCZQ1 RP-HPLC MS analyses have been performed on a Waters ZQ2000 mass spectrometer, HP1 100 HPLC + DAD (Wavelength range ( nm ): 210 to 500) and Gilson 215 Autosampler. 25 Mobile Phases: A: Water with 0.1% TFA B: MeOH Time in min %A %B Flowrate in ml/min 0.00 80 20 2.00 156 WO 2011/104340 PCT/EP2011/052813 1.7 0 100 2.00 2.50 0 100 2.00 2.60 80 20 2.00 Stationary phase: Waters, Sunfire, C18, 3,5 pm, 4,6 X 50 mm. 5 Column temp: 600C. Diode array detection is at the wavelength range of 210-500 nm. Method A_4 Waters ZQ 2000; Waters 1515 Pumpe; Waters PDA 996 Detektor; Waters 2747 10 Injektor DAD 200-420 nm mobile phases: A: water with 0.10% formic acid B: acetonitrile with 0.10% formic acid 15 time in min %A %B flow rate in ml/min 0.00 95 5 1.00 0.10 95 5 1.00 3.10 2 98 1.00 20 4.50 2 95 1.00 5.00 95 5 1.00 Stationary phase: X-terra MS C18; 4.6x3Omm*2.5pm Method amsistandard: 25 ZQ 2000MS; Waters 2996 PDA (210-600 nm); Waters 2525 pump; Waters 515 make up pump; Waters 2767 injector/ fraction collector, Waters columns and fluidics organizer (CFO) mobile phases: A: water with 0.20% trifluoroacetic acid 30 B: Methanol time in min %A %B flow rate in ml/min 0.00 72 18 55.00 2.00 72 18 55.00 157 WO 2011/104340 PCT/EP2011/052813 2.50 62 38 55.00 9.50 18 72 55.00 10.00 0 100 55.00 12.00 0 100 55.00 5 12.50 0 100 0 Stationary phase: X-terra MS C18; 30x100mm*5pm Temperature 250C Method amslunpolarl: 10 ZQ 2000MS; Waters 2996 PDA (210-600 nm); Waters 2525 pump; Waters 515 make up pump; Waters 2767 injector/ fraction collector, Waters columns and fluidics organizer (CFO) mobile phases: A: water with 0.20% trifluoroacetic acid 15 B: Methanol time in min %A %B flow rate in ml/min 0.00 59 41 55.00 2.00 59 41 55.00 2.50 49 51 55.00 20 9.50 5 95 55.00 10.00 0 100 55.00 12.00 0 100 55.00 12.50 0 100 0 Stationary phase: X-terra MS C18; 30x100mm*5pm 25 Temperature 250C Method 002_CCZQ4 RP-HPLC MS analyses have been performed on a Waters ZQ2000 mass spectrometer, HP1 100 HPLC + DAD (Wavelength range ( nm ): 210 to 500) and Gilson 215 Autosampler. Mobile Phases: A: Water with 0.1% TFA 158 WO 2011/104340 PCT/EP2011/052813 B: MeOH Time in min %A %B Flowrate in ml/min 0.00 95 5 1.50 1.3 0 100 1.50 5 2.50 0 100 1.50 2.60 95 5 1.50 Stationary phase: Waters, Sunfire, C18, 3,5 pm, 4,6 X 50 mm. Column temp: constant at 400C. Diode array detection is at the wavelength range of 210-500 nm. 10 Method 003_CCZQ6 RP-HPLC MS analyses have been performed on a Waters ZQ2000 mass spectrometer, ,Alliance 2695, PDA2996 HP1 100 HPLC + DAD (Wavelength range ( nm ): 210 to 500) and As 2700 Mobile Phases: A: Water with 0.1% TFA B: MeOH 15 Time in min %A %B Flowrate in ml/min 0.00 95 5 1.50 1.3 0 100 1.50 3.00 0 100 1.50 3.40 95 5 1.50 20 Stationary phase: Waters, Sunfire, C18, 3,5 pm, 4,6 X 50 mm. Column temp: constant at 400C. Diode array detection is at the wavelength range of 210-500 nm. 25 Method 004_CCZQ6 RP-HPLC MS analyses have been performed on a Waters ZQ2000 mass spectrometer,Alliance 2695, PDA2996 DAD (Wavelength range ( nm ): 210 to 500) and 2700 AS Mobile Phases: 159 WO 2011/104340 PCT/EP2011/052813 A: Water with 0.1% TFA B: MeOH Time in min %A %B Flowrate in ml/min 0.00 80 20 2 5 1.7 0 100 2 2.5 0 100 2 2.6 80 20 2 Stationary phase: Waters, Sunfire, C18, 3,5 pm, 4,6 X 50 mm. Column temp: 600C. 10 Diode array detection is at the wavelength range of 210-500 nm. Method 004_CCZQ7 RP-HPLC MS analyses have been performed on a Waters ZQ2000 mass spectrometer, DAD (Wavelength range ( nm ): 210 to 500) and 2700 AS Mobile Phases: A: Water with 0.15% TFA 15 B: MeOH Time in min %A %B Flowrate in ml/min 0.00 95 5 1.5 1.5 95 5 1.5 2.0 0 100 1.5 20 Stationary phase: Xbridge C18, 3,5 pm, 4,6 X 50 mm. Column temp: 400C. Diode array detection is at the wavelength range of 210-500 nm. Method 003_CCZQ7 RP-HPLC MS analyses have been performed on a Waters ZQ2000 mass spectrometer, DAD (Wavelength range ( nm ): 210 to 500) and 2700 AS 25 Mobile Phases: A: Water with 0.032% NH40H B: MeOH 160 WO 2011/104340 PCT/EP2011/052813 Time in min %A %B Flowrate in ml/min 0.00 95 5 1.5 1.5 95 5 1.5 2.0 0 100 1.5 5 Stationary phase: Xbridge C18, 3,5 pm, 4,6 X 50 mm. Column temp: 400C. Diode array detection is at the wavelength range of 210-500 nm. Method 007_CCZQ5 RP-HPLC MS analyses have been performed on a Waters ZQ2000 mass spectrometer, Alliance 2790 DAD (Wavelength range ( nm ): 210 to 500) and 2700 AS 10 Mobile Phases: A: Water with 0.1% TFA B: MeOH Time in min %A %B Flowrate in ml/min 0.00 80 20 2 15 1.7 0 100 2 2.5 0 100 2 2.6 80 20 2 Stationary phase: Waters, Sunfire C18, 3,5 pm, 4,6 X 50 mm. 20 Column temp: 600C. Diode array detection is at the wavelength range of 210-500 nm. Method 007_CCZQ7 RP-HPLC MS analyses have been performed on a Waters ZQ2000 mass spectrometer, Alliance 2790 DAD (Wavelength range ( nm ): 210 to 500) and 2700 AS Mobile Phases: 25 A: Water with 0.1% TFA B: MeOH Time in min %A %B Flowrate in ml/min 161 WO 2011/104340 PCT/EP2011/052813 0.00 80 20 2 1.7 0 100 2 2.5 0 100 2 2.6 80 20 2 5 Stationary phase: Waters, Sunfire C18, 3,5 pm, 4,6 X 50 mm. Column temp: 600C. Diode array detection is at the wavelength range of 210-500 nm. 10 Method M2-SB-C18 RP-HPLC MS analyses have been performed on a Agilent 1200, MS G6140A, binare Pumpe, DAD 190-400 nm Mobile Phases: A: Water with 0.1% TFA B: MeOH Time in min %A %B Flowrate in ml/min 15 0.00 90 10 3 1.8 0 100 3 2.0 0 100 3 2.15 90 10 3 2.35 90 10 3 20 Stationary phase: Agilent, Stable Bond SB-C18, 1,8 pm, 4,6 X 30 mm. Diode array detection is at the wavelength range of 190-400 nm. Method W001_001 column: XBridge 01 8, 4.6 x 30 mm, 2.5 pm Supplier Waters time [min] % Sol % Sol Flow [mi/mini Temp [00] [H20,O.1%TFA] [Methanol,O. 1 %TFA1 0.0 95 5 4 60 0.05 95 5 3 60 2.05 0 100 3 60 2.10 0 100 4 60 2.35 0 100 4 60 162

Claims (21)

1. A compound of general formula 5 R1 X o R2 NH R3 N R4 N S N S (I), wherein 10 X is CH or N, R 1 is a hydrogen or halogen atom or CN or an C 1 .3 alkyl or CONH 2 group, R 2 is a straight-chained or branched C 1 . 6 alkyl group which is independently 15 substituted with one or two fluorine atoms, or one or two trifluoromethyl, tetrahydropyranyl, cyclopropyl, H 2 N-CO-, R 5 NHCO- or (R 5 ) 2 N-CO- groups, wherein the above-mentioned cyclopropyl group may be substituted with one or two F or -CH 2 -CN, 20 and wherein the two R 5 groups together with the N atom to which they are attached may form a 4- to 8-membered ring, in which a carbon atom may be replaced by a 0, S, SO, SO 2 and/or which may be substituted with OH, NH 2 , N(C 1 . 3 - alkyl) 2 , NH(C 1 . 3 alkyl), CF 3 orC 1 . 3 -alkyl, 25 or a straight-chained or branched C 2 - 6 alkyl group which is independently substituted in position 2 to 6 with one or two hydroxy, C1-3 alkoxy, amino, CN, R 5 NH-, (R 5 ) 2 N-, R 5 0CONH-, R 5 CONH-, R 5 SO 2 NH-, R 5 NHCONH- groups, 163 WO 2011/104340 PCT/EP2011/052813 wherein R 5 is a C1-5 alkyl group, preferably a C1.4 alkyl group, more preferably Me, i-Pr or t-Bu, each optionally substituted with one CF 3 , NH 2 , NH(C 1 . 3 alkyl), N(C1.3.alkyl) 2 or MeO- group, 5 an wherein the hydrogen atoms of any of the above-mentioned NH moiety may be replaced by methyl, R 3 is a C 1 -2alkyl group and 10 R 4 is a carboxy, C1.3 alkoxy-carbonyl, -CONH 2 , -CONHR 7 , -CONH-OR 7 , -CONH S0 2 R 7 or -CO-NH-L-R 6 group, wherein L is a -(CH 2 )n-, -CH 2 -C-C-CH 2 -, or R 6 is OH, -NH 2 , -NHR 7 , -N(R 7 ) 2 , -NH-C0 2 R 7 or a 3- to 6-membered cyclic 15 amine such as pyrrolidine or piperidine, n is 2 or 3 and R 7 is C 1 . 4 alkyl, preferably methyl, 20 or a salt thereof.

2. A compound of formula (I) according to claim 1, wherein 25 X, R 1 , R 2 and R4 are defined as in claim 1 and R 3 is methyl, 30 or a salt thereof. 164 WO 2011/104340 PCT/EP2011/052813

3. A compound of formula (1) according to claim 1 or 2, wherein R 2 to R 4 are defined as in claim 1 and 5 X is CH and R 1 is a fluorine atom, or a salt thereof. 10

4. A compound of formula (1) according to claim 1 or 2, wherein R 2 to R 4 are defined as in claim 1 and 15 X is N and R 1 is a hydrogen atom, 20 or a salt thereof.

5. A compound of formula (1) according to any one of claims 1 to 4, wherein X, R 1 , R 3 and R 4 are defined as in any one of claims 1 to 4 and 25 R 2 is selected from: (dimethylamino)-carbonylmethyl, ethyl, 2-amino-ethyl, 1-(trifluoromethyl)-ethyl; isopropyl optionally substituted in position 2 with ethoxycarbonyl, amino or tert 30 butyloxycarbonylamino; 2,2'-diamino-isopropyl, 2,2'-difluoro-isopropyl, 2,2'-di-(ethoxy)-isopropyl, 2,2'-bis (tert-butyloxycarbonylamino)-isopropyl, 2-[2'-(trifluoromethyl)-ethylamino]-isopropyl, 3-amino-1-methyl-propyl, 3-(dimethylamino)-1-methyl-propyl, 165 WO 2011/104340 PCT/EP2011/052813 3-hydroxy-1,3-dimethyl-butyl, or a fluor-containing residue such as 1,3-difluoropropan-2-yl, 1,1,1-trifluoropropan-2-yl or 1,1-difluoroethyl, 5 or salt thereof.

6. A compound of formula (1) according to any one of claims 1 to 4, wherein X, R 1 , R 3 and R 4 are defined as in any one of claims 1 to 4 and 10 R 2 is selected from:isopropyl and isobutyl optionally substituted in position 2 or 3 with ethoxycarbonyl, amino, tert-butyloxycarbonylamino or methylsulfonylamino or a salt thereof. 15

7. A compound of formula (1) according to any one of claims 1 to 6, wherein X, R 1 to R 3 are defined as in any one of claims 1 to 6 and R 4 is selected from: carboxy, C1-3 alkoxy-carbonyl, aminocarbonyl, N-(C 1 3 alkyl)-aminocarbonyl or N,N [di-(C 1 . 3 alkyl)]-aminocarbonyl group, 20 wherein the alkyl moiety of the above-mentioned N-(C 1 3 alkyl)-aminocarbonyl and N,N-[di-(C 1 .3 alkyl)]-aminocarbonyl groups may optionally be terminally substituted with a hydroxy, amino, N-(C 1 .3 alkyl)-amino or N,N-[di-(C 1 .3 alkyl)] amino group, 25 or a salt thereof.

8. A compound of formula (1) according to any one of claims 1 to 6, wherein 30 X, R 1 to R 3 are defined as in any one of claims 1 to 6 and R 4 is selected from: aminocarbonyl, N-methyl-aminocarbonyl; 166 WO 2011/104340 PCT/EP2011/052813 N-ethyl-aminocarbonyl terminally substituted in the ethyl moiety with hydroxy or N,N dimethylamino; N-(n-propyl)-aminocarbonyl terminally substituted in the n-propyl moiety with N,N dimethylamino; 5 carboxy or methoxycarbonyl, or a salt thereof. 10

9. Compound of formula (1) according to claim 1 selected from: a) Methyl 4-(2-(1-aminopropan-2-yloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3 d]pyrimidine-6-carboxylate, 15 b) 4-(2-(1 -Aminopropan-2-yloxy)-4-fluorophenylamino)-N-5-methylthieno[2,3 d]pyrimid ine-6-carboxamide, c) Methyl 4-(4-fluoro-(2-(1-methylsulfonamido)propan-2-yloxy)phenylamino)-5 methyl-th ieno[2,3-d]pyrimid ine-6-carboxylate, 20 d) 4-(2-(1 -Aminopropan-2-yloxy)-4-fluorophenylamino)-5-methylthieno[2,3 d]pyrimid ine-6-carboxamide, e) 4-(2-(1 -Aminopropan-2-yloxy)-4-fluorophenylamino)-5-methy-Ithieno[2,3 25 d]pyrimidine-6-carboxylic acid, f) Methyl 4-(2-(4-aminobutan-2yloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3 d]pyrimidine-6-carboxylate, 30 g) Methyl 4-(4-fluoro-2-(4-(methylsulfonamido)butan-2yloxy)phenylamino)-5-methyl thieno[2,3-d]pyrimidine-6-carboxylate , 167 WO 2011/104340 PCT/EP201 1/052813 h) 4-(2-(4-Ami nobutan-2yloxy)pyrid in-3ylami no)-5-methylth ieno[2,3-d] pyri mid ine-6 carboxylate, i) N-(3-(Dimethylamino)propyl)-4-(4-fluoro-2-(4-hydroxy-4-methylpentan-2 5 yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxamide, j) 5-Methyl-4-(2-(1 ,1,1 -trifluoropropan-2yloxy)pyridin-3-ylamino)thieno[2,3 d]pyrimidine-6-carboxylic acid, 10 k) 5-Methyl-4-(2-(1 ,1,1 -trifluoropropan-2yloxy)pyridin-3-ylamino)thieno[2,3 d] pyri mid i ne-6-carboxamide, 1) N-Methyl- 5-methyl-4-(2-(1 ,1,1 trifluoropropan-2-yloxy)pyridin-3-ylamino)thieno[2,3 d] pyri mid i ne-6-N-methyl carboxamide, 15 m) 4-(2-(1 ,3-Difluoropropan-2-yloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3 d] pyri mid i ne-6-carboxamide, n) N-Methyl-4-(2-(1 ,3-difluoropropan-2-yloxy)-4-fluorophenylamino) 20 5-methyl -th ieno[2,3d]pyri mid ine-6-carboxamide, o) 4-(2-(1 ,3-Difluoropropan-2-yloxy)-4-fluorophenylamino)-N-(3 (d i methyl ami no)propyl)-5-methyl-th ieno[2,3-d]-pyri mid i ne-6-carboxamide, 25 p) 4-(2-(1 ,3-Difluoropropan-2-yloxy)-4-fluorophenylamino) N-(2-(dimethylamino)ethyl)-5-methylthieno[2,3-d] pyrimidine-6-carboxamide, q) 4-(2-(1 ,3-Difluoropropan-2-yloxy)-4-fluorophenylamino)-N-(2-(hydroxyethyl)-5 methylthieno[2,3-d] pyri mid ine-6-carboxamide, 30 r) 4-(2-(1 ,3-Difluoropropan-2-yloxy)-4-fluorophenylamino)-5-methyl-N-(3-(pyrrolidin-1 yI )propyl )th ieno[2,3-d] pyri mid i ne-6-carboxa mide, 168 WO 2011/104340 PCT/EP2011/052813 s) N-((trans)-2-Aminocyclopropyl)-4-(2-(1,3-difluoropropan-2-yloxy)-4 fluorophenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxamide, t) 4-(2-(2-Fluoropropoxy)pyridin-3-ylamino)-N-(2-hydroxyethyl)-5-methylthieno[2,3 5 d]pyrimidine-6-carboxamide, u) 4-(2-(2,2-Difluoroethoxy)pyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6 carboxylic acid, 10 v) 4-(2-(2,2-Difluoroethoxy)pyridin-3-ylamino)-5-methyl-thieno[2,3-d]pyrimidine-6 carboxamide, w) 4-(2-(2,2-Difluoroethoxy)pyridin-3-ylamino)-N-(3-(dimethylamino)propyl)-5 methylth ieno[2,3-d]pyrimidine-6-carboxamide, 15 x) 4-(2-(1 -(Ethylamino)-1 -oxopropan-2-yloxy)-4-fluorophenylamino)-N,5 dimethylthieno[2,3-d]pyrimidine-6-carboxamide and y) 4-(2-(1 -(Ethylamino)-1 -oxopropan-2-yloxy)-4-fluorophenylamino)-N,5 20 dimethylthieno[2,3-d]pyrimidine-6-carboxamide, or a salt thereof. 25

10. A pharmaceutically acceptable salt of a compound according to any one of claims 1 to 9.

11. Pharmaceutical composition comprising a compound according to any one of 30 claims 1 to 9 or a salt according to claim 10 and optionally a pharmaceutically acceptable carrier. 169 WO 2011/104340 PCT/EP2011/052813

12. Pharmaceutical composition according to claim 11 further comprising an additional therapeutic agent. 5

13. Pharmaceutical composition according to claim 12 wherein the additional therapeutic agent is selected from an antidiabetic agent, a lipid lowering agent, a cardiovascular agent, an antihypertensive agent, a diuretic agent, a thrombocyte aggregation inhibitor, an antineoplastic agent or an anti-obesity agent. 10

14. Compound as defined in any one of claims 1 to 9 or a salt according to claim 10 for use in inhibiting the activity of the kinase activity of Mnk1 or Mnk2 (Mnk2a, Mnk2b) or variants thereof. 15

15. Compound as defined in any one of claims 1 to 9 or a salt according to claim 10 for use in the prophylaxis or therapy of metabolic diseases, hematopoietic disorders, neurodegenerative diseases, kidney damage, inflammatory 20 disorders and cancer and their consecutive complications and diseases.

16. Compound according to any one of claims 1 to 9 or a salt according to claim 10 for use in the prophylaxis or therapy of metabolic diseases of the 25 carbohydrate and/or lipid metabolism and their consecutive complications and disorders.

17. Compound according to claim any one of claims 1 to 9 or a salt according to 30 claim 10 for use in the prophylaxis or therapy of diabetes.

18. Compound according to any one of claims 14 to 17 for concomitant or 170 WO 2011/104340 PCT/EP2011/052813 sequential administration to a patient in combination with an additional therapeutic agent. 5

19. Compound as defined in any of claims 1 to 9 or a salt according to claim 10 for use in treating or preventing cytokine related disorders.

20. Compound according to claim 19 for concomitant or sequential administration to a patient in combination with an additional therapeutic agent. 10

21. Compound according to claim 20, wherein the additional therapeutic agent is selected from a histamine antagonist, a bradikinin antagonist, serotonin antagonist, leukotriene, an anti-asthmatic, an NSAID, an antipyretic, a 15 corticosteroid, an antibiotic, an analgetic, a uricosuric agent, chemotherapeutic agent, an anti gout agent, a bronchodilator, a cyclooxygenase-2 inhibitor, a steroid, a 5-lipoxygenase inhibitor, an immunosuppressive agent, a leukotriene antagonist, a cytostatic agent, an antineoplastic agent, a mTor inhibitor, a Tyrosine kinase inhibitor, antibodies or fragments thereof against cytokines 20 and soluble parts (fragments) of cytokine receptors. 171